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1
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Liu H, Li Z, Xu X, Xu B, Li Z. Network pharmacology and in vitro analyses reveal EGCG inhibits breast cancer progression via suppression of the EGFR/Src pathway. Biochem Biophys Res Commun 2025; 769:151942. [PMID: 40359763 DOI: 10.1016/j.bbrc.2025.151942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 04/08/2025] [Accepted: 05/04/2025] [Indexed: 05/15/2025]
Abstract
Breast cancer (BRCA) has emerged as a significant threat to women's health. Epigallocatechin gallate (EGCG) has shown promising therapeutic potential. However, its mechanisms of action are not yet fully understood. This study employed a network pharmacology (NP) approach to investigate the key targets and signaling pathways regulated by EGCG in BRCA, and validated the findings through cell experiments. Our comprehensive analysis identified 10 key targets of EGCG, suggesting that EGCG may inhibit the EGFR/Src pathway. Consistently, our cell experiments revealed that EGCG could significantly inhibit the migration, invasion, and proliferation of BRCA cells. Furthermore, EGCG downregulated the protein levels of EGFR, Src, PI3K, Akt, STAT3, and Bcl2. These experimental findings support the results of the NP analysis. In conclusion, our NP and in vitro studies indicate that EGCG inhibits BRCA progression by suppressing the EGFR/Src pathway and its downstream signals transduction including the PI3K/Akt and STAT3/Bcl2 pathways.
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Affiliation(s)
- Huiying Liu
- The Institute of Translational Medicine, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China; The Jiangxi Province Key Laboratory of Precision Cell Therapy, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China; Department of Rehabilitation Medicine, The Department of Rehabilitation Medicine, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
| | - Zhiqiang Li
- The Institute of Translational Medicine, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China; The Jiangxi Province Key Laboratory of Precision Cell Therapy, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China; Department of Rehabilitation Medicine, The Department of Rehabilitation Medicine, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
| | - Xiaohui Xu
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Shandong, 266000, China
| | - Binwu Xu
- The Institute of Translational Medicine, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China; The Jiangxi Province Key Laboratory of Precision Cell Therapy, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China; Department of Rehabilitation Medicine, The Department of Rehabilitation Medicine, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
| | - Zhipeng Li
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang, 330047, China.
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2
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Dong Z, Chen H, Yang Y, Hao H. Research on the optimization model of anti-breast cancer candidate drugs based on machine learning. Front Genet 2025; 16:1523015. [PMID: 40276676 PMCID: PMC12018315 DOI: 10.3389/fgene.2025.1523015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 03/31/2025] [Indexed: 04/26/2025] Open
Abstract
Breast cancer is one of the most common malignancies among women globally, with its incidence rate continuously increasing, posing a serious threat to women's health. Although current treatments, such as drugs targeting estrogen receptor alpha (ERα), have extended patient survival, issues such as drug resistance and severe side effects remain widespread. This study proposes a machine learning-based optimization model for anti-breast cancer candidate drugs, aimed at enhancing biological activity and optimizing ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) properties through multi-objective optimization. Initially, grey relational analysis and Spearman correlation analysis were performed on the molecular descriptors of 1,974 compounds, identifying 91 key descriptors. A Random Forest model combined with Shapley Additive Explanations (SHAP) values was then used to further select the top 20 descriptors with the greatest impact on biological activity. The constructed Quantitative Structure-Activity Relationship (QSAR) model, using algorithms such as LightGBM, Random Forest, and XGBoost, achieved an R2 value of 0.743 for biological activity prediction, demonstrating strong predictive performance. Additionally, a multi-model fusion strategy and Particle Swarm Optimization (PSO) algorithm were employed to optimize both biological activity and ADMET properties, thereby improving the prediction of Caco-2, CYP3A4, hERG, HOB, and MN properties. For example, the best model for predicting Caco-2 achieved an F1 score of 0.8905, while the model for predicting CYP3A4 reached an F1 score of 0.9733. This multi-objective optimization model provides a novel and efficient tool for drug development, offering significant improvements in both biological activity and pharmacokinetic properties, with practical implications for the optimization of future anti-breast cancer drugs.
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Affiliation(s)
- Zhou Dong
- School of Information Engineering, Xi’an Eurasia University, Xi’an, China
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Kim N, Lukong KE. Treating ER-positive breast cancer: a review of the current FDA-approved SERMs and SERDs and their mechanisms of action. Oncol Rev 2025; 19:1564642. [PMID: 40275985 PMCID: PMC12018393 DOI: 10.3389/or.2025.1564642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Accepted: 03/31/2025] [Indexed: 04/26/2025] Open
Abstract
Breast cancer is one of the most significant causes of mortality among women and the second most prevalent cancer worldwide. Estrogen receptor (ER)-positive breast cancers are the most common molecular subtype of breast cancer, comprising about 70% of breast carcinoma diagnoses worldwide. Endocrine therapy is the foremost strategy for the treatment of ER-positive breast cancer. In the United States, the Food and Drug Administration (FDA) has approved endocrine therapies for ER-positive breast cancers that include selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators/degraders (SERDs) and aromatase inhibitors (AIs). The approved SERMS, tamoxifen, toremifene and raloxifene, are the gold-standard treatments. The only FDA-approved SERD available for treating ER and hormone-positive breast cancers is fulvestrant, and various generations of AIs, including exemestane, letrozole, and anastrozole, have also received FDA approval. Herein, we review the major FDA-approved SERMs and SERDs for treating ER-positive breast cancer, focusing on their mechanisms of action. We also explore molecular events that contribute to the resistance of these drugs to endocrine therapies and combinational strategies with drugs such as cyclin-dependant kinases 4/6 (CDK4/6) inhibitors in clinical trials to combat endocrine drug resistance.
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Affiliation(s)
| | - Kiven Erique Lukong
- Biochemistry, Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
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4
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Yan Z, Huang A, Ma D, Hong C, Zhang S, He L, Rao H, Luo S. ATP6AP1 promotes cell proliferation and tamoxifen resistance in luminal breast cancer by inducing autophagy. Cell Death Dis 2025; 16:201. [PMID: 40133274 PMCID: PMC11937278 DOI: 10.1038/s41419-025-07534-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 03/01/2025] [Accepted: 03/12/2025] [Indexed: 03/27/2025]
Abstract
Autophagy is a highly conserved cellular process essential for maintaining cellular homeostasis and influencing cancer development. Lysosomal acidification and autophagosome-lysosome fusion are two important steps of autophagy degradation that are tightly regulated. Although many key proteins that regulate these two events have been identified, the effector proteins that co-regulate both steps remain to be explored. ATP6AP1, an accessory subunit of V-ATPase, plays a critical role in the assembly and regulation of V-ATPase. However, the function of ATP6AP1 in autophagy remains unknown, and the role of ATP6AP1 in cancer is still poorly understood. In this study, we found that ATP6AP1 is overexpressed in luminal breast cancer tissues and promotes the proliferation and tamoxifen resistance of luminal breast cancer cells both in vitro and in vivo. We also observed that high ATP6AP1 expression correlates with poor overall patient survival. Our research further revealed that ATP6AP1 enhances tamoxifen resistance by activating autophagy. Mechanistically, ATP6AP1 promotes autophagy by regulating both lysosomal acidification and autophagosome-lysosome fusion. Remarkably, ATP6AP1 induces lysosomal acidification through the regulation of V-ATPase assembly and facilitates autophagosome-lysosome fusion by enhancing the interaction between Rab7 and the HOPS complex. Together, our studies identify ATP6AP1 as a crucial regulator of autophagy, potentially serving as a valuable prognostic marker or therapeutic target in human luminal breast cancer.
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Affiliation(s)
- Zhengwei Yan
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors; Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
- Department of Biochemistry, School of Medicine, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Aidi Huang
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors; Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
- Department of Pathology and Institute of Molecular Pathology, Jiangxi Provincial Key Laboratory for Precision Pathology and Intelligent Diagnosis, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Dongwen Ma
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors; Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
- Department of Pathology and Institute of Molecular Pathology, Jiangxi Provincial Key Laboratory for Precision Pathology and Intelligent Diagnosis, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Chenao Hong
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors; Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
- Department of Pathology and Institute of Molecular Pathology, Jiangxi Provincial Key Laboratory for Precision Pathology and Intelligent Diagnosis, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Shengmiao Zhang
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors; Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
- Department of Pathology and Institute of Molecular Pathology, Jiangxi Provincial Key Laboratory for Precision Pathology and Intelligent Diagnosis, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Luling He
- Department of Biochemistry, School of Medicine, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Hai Rao
- Department of Biochemistry, School of Medicine, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, 518055, China.
| | - Shiwen Luo
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors; Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China.
- Department of Pathology and Institute of Molecular Pathology, Jiangxi Provincial Key Laboratory for Precision Pathology and Intelligent Diagnosis, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China.
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5
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Sharma D, Dhobi M, Lather V, Pandita D. An insight into the therapeutic effects of isoliquiritigenin in breast cancer. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:9503-9519. [PMID: 39007925 DOI: 10.1007/s00210-024-03282-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 07/02/2024] [Indexed: 07/16/2024]
Abstract
Breast cancer ranks as the most widespread malignant condition in women, emerging as a primary contributor to mortality. The primary challenges in cancer treatments involve undesirable side effects. Therefore, exploring natural compounds as additional therapy could provide valuable insights. Isoliquiritigenin (ILN), an isoflavonoid featuring a chalcone moiety primarily sourced from Glycyrrhiza species, has garnered increasing interest in breast cancer research. This review aims to provide a comprehensive understanding of ILN's mechanisms of action in breast cancer, drawing from a range of in vitro and in vivo studies. ILN primarily acts by inhibiting angiogenesis, aromatase, inflammation, and cell proliferation, and preventing invasion and metastasis. Mechanistically, it downregulates miR-374a, phosphoinositide-3-kinase-protein kinase B/Akt, maternal embryonic leucine zipper kinase, vascular endothelial growth factor, and estrogen receptor protein levels, and causes enhancement of Wnt inhibitory factor-1, and Unc-51-like kinase 1 expression to treat breast cancer. ILN emerges as a promising natural option, offering therapeutic advantages with minimal side effects. However, it is important to note that current research on ILN is primarily limited to preclinical models, underscoring the need for further investigation to validate its potential efficacy.
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Affiliation(s)
- Divya Sharma
- School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, Sector-III, Pushp Vihar, Government of NCT of Delhi, New Delhi, 110017, India
| | - Mahaveer Dhobi
- School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, Sector-III, Pushp Vihar, Government of NCT of Delhi, New Delhi, 110017, India.
| | - Viney Lather
- Amity Institute of Pharmacy, Amity University Uttar Pradesh, Sector 125, Noida, 201313, India.
| | - Deepti Pandita
- Department of Pharmaceutics, Delhi Institute of Pharmaceutical Sciences & Research (DIPSAR) Delhi Pharmaceutical Sciences and Research University, Sector-III, Pushp Vihar, Government of NCT of Delhi, New Delhi, 110017, India.
- Centre for Advanced Formulation Technology (CAFT), Delhi Pharmaceutical Sciences and Research University, Sector-III, Pushp Vihar, Government of NCT of Delhi, New Delhi, 110017, India.
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6
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Sharma B, Dhiman C, Hasan GM, Shamsi A, Hassan MI. Pharmacological Features and Therapeutic Implications of Plumbagin in Cancer and Metabolic Disorders: A Narrative Review. Nutrients 2024; 16:3033. [PMID: 39275349 PMCID: PMC11397539 DOI: 10.3390/nu16173033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 08/30/2024] [Accepted: 09/06/2024] [Indexed: 09/16/2024] Open
Abstract
Plumbagin (PLB) is a naphthoquinone extracted from Plumbago indica. In recent times, there has been a growing body of evidence suggesting the potential importance of naphthoquinones, both natural and artificial, in the pharmacological world. Numerous studies have indicated that PLB plays a vital role in combating cancers and other disorders. There is substantial evidence indicating that PLB may have a significant role in the treatment of breast cancer, brain tumours, lung cancer, hepatocellular carcinoma, and other conditions. Moreover, its potent anti-oxidant and anti-inflammatory properties offer promising avenues for the treatment of neurodegenerative and cardiovascular diseases. A number of studies have identified various pathways that may be responsible for the therapeutic efficacy of PLB. These include cell cycle regulation, apoptotic pathways, ROS induction pathways, inflammatory pathways, and signal transduction pathways such as PI3K/AKT/mTOR, STAT3/PLK1/AKT, and others. This review aims to provide a comprehensive analysis of the diverse pharmacological roles of PLB, examining the mechanisms through which it operates and exploring its potential applications in various medical conditions. In addition, we have conducted a review of the various formulations that have been reported in the literature with the objective of enhancing the efficacy of the compound. However, the majority of the reviewed data are based on in vitro and in vivo studies. To gain a comprehensive understanding of the safety and efficacy of PLB in humans and to ascertain its potential integration into therapeutic regimens for cancer and chronic diseases, rigorous clinical trials are essential. Finally, by synthesizing current research and identifying gaps in knowledge, this review seeks to enhance our understanding of PLB and its therapeutic prospects, paving the way for future studies and clinical applications.
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Affiliation(s)
- Bhoomika Sharma
- Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Chitra Dhiman
- Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Gulam Mustafa Hasan
- Department of Basic Medical Science, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Anas Shamsi
- Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman P.O. Box 346, United Arab Emirates
| | - Md Imtiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
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7
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Pandi E, Proskhan BF, Kunjiappan S, Sundar K, Balakrishnan V. Fabrication, Characterization and Evaluation of Gallic Acid-Encapsulated Curdlan Gum Nanoparticles with Potential Application for Breast Cancer Treatment. JOURNAL OF POLYMERS AND THE ENVIRONMENT 2024; 32:3071-3088. [DOI: 10.1007/s10924-023-03139-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 11/28/2023] [Indexed: 01/06/2025]
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8
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Duduyemi BM, Ayibor WG, Agyemang-Yeboah F. Tissue Microarray Immunohistochemical Staining for Androgen Receptor in Breast Cancer in a Ghanaian Cohort. Ann Afr Med 2024; 23:452-458. [PMID: 39034572 PMCID: PMC11364299 DOI: 10.4103/aam.aam_83_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 10/20/2023] [Accepted: 11/27/2023] [Indexed: 07/23/2024] Open
Abstract
BACKGROUND Despite the advancement in therapy, breast cancer still remains the most common malignancy in women globally due in part to its heterogeneity. Triple-negative breast cancer (TNBC) represents up to 20% of all breast cancer variants, an aggressive disease with poorer outcomes compared to other breast cancer subtypes. No targeted therapies are currently approved for TNBC, and newer treatment approaches are seriously needed. Androgen receptor (AR), another hormonal receptor, is often expressed in breast cancer, and its role depends on the relative levels of circulating estrogens and androgens. This study aimed to assess the expression of AR in breast cancer in a tertiary hospital in Ghana. METHODOLOGY Immunohistochemical staining for AR was performed on tissue microarray (TMA) blocks, of which estrogen receptor, progesterone receptor, and Her-2/neu had already been done. 197 cases were suitable for the study. Results from the immunostaining were analyzed using the SPSS version 23 for descriptive statistics and correlations (χ2 and Pearson tests). RESULTS 197 TMA cases were used. TNBCs constitute 61.9% of the cancers. The majority of these tumors were grade III, ductal carcinoma NST. The mean age was 49.86 ± 14.09, and the modal age group was 40-49 years. Our cases showed 23% AR expression in triple-negative cancers. The study also established that AR is more frequently expressed in low-grade tumors compared to high-grade ones. CONCLUSION There is an appreciable level of AR expression in our cases; however, most are quadruple negative. However, AR is more frequently expressed in low-grade tumors than high-grade ones.
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Affiliation(s)
- Babatunde M. Duduyemi
- Department of Pathology, School of Medicine and Dentistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
- Department of Pathology, University of Sierra Leone Teaching Hospitals Complex, Freetown, Sierra Leone
| | - William G. Ayibor
- Department of Pathology, School of Medicine and Dentistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Francis Agyemang-Yeboah
- Department of Molecular Medicine, School of Medicine and Dentistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
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Fiocchetti M, Raimondi S, Bastari G, Bartoloni S, Marino M, Acconcia F. Characterization of ERα Signaling to Cell Proliferation Induced by Chronic and Pulsatile E2 Stimulation in 2D and 3D Cell Cultures. J Cell Biochem 2024; 125:e30610. [PMID: 38860517 DOI: 10.1002/jcb.30610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 03/19/2024] [Accepted: 05/24/2024] [Indexed: 06/12/2024]
Abstract
17β-estradiol is a hormone that plays a vital role in human physiology. It acts through estrogen receptors, specifically estrogen receptor α and estrogen receptor β, and its action is determined by the pulsatile secretion in the bloodstream. 17β-estradiol affects cell proliferation, and dysregulation of 17β-estradiol:estrogen receptor α signaling contribute to the development of breast cancer. Previous research on 17β-estradiol:estrogen receptor α signaling has primarily used two-dimensional cell cultures, which do not fully recapitulate the complexity of tumors that exist in a three-dimensional environment and do not consider the pulsatile nature of this hormone. To address these limitations, we studied 17β-estradiol:estrogen receptor α signaling in cell proliferation using both two-dimensional and three-dimensional breast cancer cell culture models under continuous and pulsatile stimulation conditions. Results revealed that breast cancer cells grown in an alginate-based three-dimensional matrix exhibited similar responsiveness to 17β-estradiol compared with cells grown in conventional two-dimensional culture plates. 17β-estradiol induced the expression of proteins containing estrogen response element in the three-dimensional model. The efficacy of the antiestrogen drugs fulvestrant (ICI182,280) and 4OH-tamoxifen was also demonstrated in the three-dimensional model. These results support the use of the three-dimensional culture model for studying tumor response to drugs and provide a more realistic microenvironment for such studies. Furthermore, the study revealed that a brief 5-min exposure to 17β-estradiol triggered a physiological response comparable with continuous hormone exposure, suggesting that the cellular response to 17β-estradiol is more important than the continuous presence of the hormone. In conclusion, the study demonstrates that the alginate-based three-dimensional culture model is suitable for studying the effects of 17β-estradiol and antiestrogen drugs on breast cancer cells, offering a more realistic representation of tumor-microenvironment interactions. The results also highlight the importance of considering the physiological importance of the temporal dynamics in studying 17β-estradiol signaling and cellular responses.
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Affiliation(s)
- Marco Fiocchetti
- Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Rome, Italy
| | - Serena Raimondi
- Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Rome, Italy
| | - Giovanna Bastari
- Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Rome, Italy
| | - Stefania Bartoloni
- Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Rome, Italy
| | - Maria Marino
- Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Rome, Italy
| | - Filippo Acconcia
- Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Rome, Italy
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10
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Sethi Y, Vora V, Anyagwa OE, Turabi N, Abdelwahab M, Kaiwan O, Chopra H, Attia MS, Yahya G, Emran TB, Padda I. Streptomyces Paradigm in Anticancer Therapy: A State-of-the Art Review. CURRENT CANCER THERAPY REVIEWS 2024; 20:386-401. [DOI: 10.2174/0115733947254550230920170230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 07/09/2023] [Accepted: 08/16/2023] [Indexed: 01/12/2025]
Abstract
Abstract:
Cancer is one of the biggest threats to human health with a global incidence of 23.6 million,
mortality of 10 million, and an estimated 250 million lost in disability-adjusted life years
(DALYs) each year. Moreover, the incidence, mortality, and DALYs have increased over the past
decade by 26.3%, 20.9%, and 16.0%, respectively. Despite significant evolutions in medical therapy
and advances in the DNA microarray, proteomics technology, and targeted therapies, anticancer drug
resistance continues to be a growing concern and invites regular discovery of potent agents. One such
agent is the microbe-producing bioactive compounds like Streptomyces, which are proving increasingly
resourceful in anticancer therapy of the future. Streptomyces, especially the species living in
extreme conditions, produce bioactive compounds with cytolytic and anti-oxidative activity which
can be utilized for producing anticancer and chemo-preventive agents. The efficacy of the derived
compounds has been proven on cell lines and some of these have already established clinical results.
These compounds can potentially be utilized in the treatment of a variety of cancers including but not
limited to colon, lung, breast, GI tract, cervix, and skin cancer. The Streptomyces, thus possess the
armory to fuel the anticancer agents of the future and help address the problem of rising resistance to
currently available anti-cancer drugs. We conducted a state-of-art review using electronic databases
of PubMed, Scopus, and Google scholar with an objective to appraise the currently available literature
on Streptomyces as a source of anti-cancer agents and to compile the clinically significant literature
to update the clinicians.
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Affiliation(s)
- Yashendra Sethi
- PearResearch, Dehradun 248001, India
- Department of Medicine, Government Doon Medical College, HNB Uttarakhand
Medical Education University, Dehradun, Uttarakhand, India
| | - Vidhi Vora
- Department of Medicine, Government Doon Medical College, HNB Uttarakhand
Medical Education University, Dehradun, Uttarakhand, India
- Department of Medicine, Lokmanya Tilak Municipal
Medical College and Sion Hospital, Maharashtra University of Health Sciences, Mumbai, Maharashtra, India
| | | | | | | | - Oroshay Kaiwan
- Department of Medicine, Government Doon Medical College, HNB Uttarakhand
Medical Education University, Dehradun, Uttarakhand, India
- Department of Medicine, Northeast Ohio Medical University, Ohio,
USA
| | - Hitesh Chopra
- Department of Biosciences, Saveetha School of Engineering, Saveetha Institute of Medical and Technical Sciences,
Chennai- 602105, Tamil Nadu, India
| | - Mohamed Shah Attia
- Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University,
Zagazig 44519, Egypt
| | - Galal Yahya
- Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Zagazig
44519, Egypt
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh
| | - Inderbir Padda
- Department of Medicine, Richmond University Medical Centre, Staten Island, NY, USA
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11
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Cantile M, Belli V, Scognamiglio G, Martorana A, De Pietro G, Tracey M, Budillon A. The role of HOTAIR in the modulation of resistance to anticancer therapy. Front Mol Biosci 2024; 11:1414651. [PMID: 38887279 PMCID: PMC11181001 DOI: 10.3389/fmolb.2024.1414651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 05/10/2024] [Indexed: 06/20/2024] Open
Abstract
Leading anti-tumour therapeutic strategies typically involve surgery and radiotherapy for locally advanced (non-metastatic) cancers, while hormone therapy, chemotherapy, and molecular targeted therapy are the current treatment options for metastatic cancer. Despite the initially high sensitivity rate to anticancer therapies, a large number of patients develop resistance, leading to a poor prognosis. The mechanisms related to drug resistance are highly complex, and long non-coding RNAs appear to play a crucial role in these processes. Among these, the lncRNA homeobox transcript antisense intergenic RNA (HOTAIR), widely implicated in cancer initiation and progression, likewise plays a significant role in anticancer drug resistance. It can modulate cell activities such as proliferation, apoptosis, hypoxia, autophagy, as well as epithelial-mesenchymal transition, thereby contributing to the development of resistant tumour cells. In this manuscript, we describe different mechanisms of antitumor drug resistance in which HOTAIR is involved and suggest its potential as a therapeutic predictive biomarker for the management of cancer patients.
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Affiliation(s)
- Monica Cantile
- Scientific Directorate, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy
| | - Valentina Belli
- Scientific Directorate, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy
| | - Giosuè Scognamiglio
- Scientific Directorate, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy
| | - Anna Martorana
- Scientific Directorate, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy
| | - Giovanna De Pietro
- Scientific Directorate, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy
| | - Maura Tracey
- Rehabilitation Medicine Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy
| | - Alfredo Budillon
- Scientific Directorate, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy
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12
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Cipolletti M, Acconcia F. PMM2 controls ERα levels and cell proliferation in ESR1 Y537S variant expressing breast cancer cells. Mol Cell Endocrinol 2024; 584:112160. [PMID: 38266771 DOI: 10.1016/j.mce.2024.112160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 11/27/2023] [Accepted: 01/12/2024] [Indexed: 01/26/2024]
Abstract
PURPOSE Metabolic reprogramming in breast cancer (BC) subtypes offers potential personalized treatment targets. Estrogen receptor α (ERα)-positive BC patients undergoing endocrine therapy (ET) can develop ET-resistant metastatic disease. Specific mutations, like Y537S in ERα, drive uncontrolled cell proliferation. Targeting mutant receptor levels shows promise for inhibiting growth in metastatic BC expressing ERα variants. Additionally, metabolic reprogramming occurs in ERα Y537S mutant cells. Consequently, we conducted a screen to identify metabolic proteins reducing intracellular levels of ERα Y537S and inhibiting cell proliferation. METHODS Nine metabolic proteins were identified in a siRNA-based screen, with phosphomannose mutase 2 (PMM2) showing the most promise. We measured the impact of PMM2 depletion on ERα stability and cell proliferation in ERα Y537S mutant cells. Additionally, we tested the effect of PMM2 reduction on the hyperactive phenotype of the mutant and its proliferation when combined with metastatic BC treatment drugs. RESULTS PMM2 emerged as a significant target due to its correlation with better relapse-free survival, overexpression in ERα-positive tumors, and its elevation in ERα Y537S-expressing cells. Depletion of PMM2 induces degradation of ERα Y537S, inhibits cell proliferation, and reduces ERα signaling. Notably, reducing PMM2 levels re-sensitizes ERα Y537S-expressing cells to certain ET drugs and CDK4/CDK6 inhibitors. Mechanistically, depletion of PMM2 leads to a reduction in ESR1 mRNA levels, resulting in decreased ERα receptor protein expression. Furthermore, the reduction of PMM2 decreases FOXA1 levels, which plays a crucial role in ERα regulation. CONCLUSIONS Our findings establish PMM2 as an innovative therapeutic target for metastatic BC expressing the ERα Y537S variant, offering alternative strategies for managing and treating this disease.
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Affiliation(s)
- Manuela Cipolletti
- Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Rome, Italy
| | - Filippo Acconcia
- Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Rome, Italy.
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13
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Bartoloni S, Pescatori S, Bianchi F, Cipolletti M, Acconcia F. Selective impact of ALK and MELK inhibition on ERα stability and cell proliferation in cell lines representing distinct molecular phenotypes of breast cancer. Sci Rep 2024; 14:8200. [PMID: 38589728 PMCID: PMC11001865 DOI: 10.1038/s41598-024-59001-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 04/05/2024] [Indexed: 04/10/2024] Open
Abstract
Breast cancer (BC) is a leading cause of global cancer-related mortality in women, necessitating accurate tumor classification for timely intervention. Molecular and histological factors, including PAM50 classification, estrogen receptor α (ERα), breast cancer type 1 susceptibility protein (BRCA1), progesterone receptor (PR), and HER2 expression, contribute to intricate BC subtyping. In this work, through a combination of bioinformatic and wet lab screenings, followed by classical signal transduction and cell proliferation methods, and employing multiple BC cell lines, we identified enhanced sensitivity of ERα-positive BC cell lines to ALK and MELK inhibitors, inducing ERα degradation and diminishing proliferation in specific BC subtypes. MELK inhibition attenuated ERα transcriptional activity, impeding E2-induced gene expression, and hampering proliferation in MCF-7 cells. Synergies between MELK inhibition with 4OH-tamoxifen (Tam) and ALK inhibition with HER2 inhibitors revealed potential therapeutic avenues for ERα-positive/PR-positive/HER2-negative and ERα-positive/PR-negative/HER2-positive tumors, respectively. Our findings propose MELK as a promising target for ERα-positive/PR-positive/HER2-negative BC and highlight ALK as a potential focus for ERα-positive/PR-negative/HER2-positive BC. The synergistic anti-proliferative effects of MELK with Tam and ALK with HER2 inhibitors underscore kinase inhibitors' potential for selective treatment in diverse BC subtypes, paving the way for personalized and effective therapeutic strategies in BC management.
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Affiliation(s)
- Stefania Bartoloni
- Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, 00146, Rome, Italy
| | - Sara Pescatori
- Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, 00146, Rome, Italy
| | - Fabrizio Bianchi
- Fondazione IRCCS Casa Sollievo Della Sofferenza, Cancer Biomarkers Unit, 71013, San Giovanni Rotondo (FG), Italy
| | - Manuela Cipolletti
- Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, 00146, Rome, Italy
| | - Filippo Acconcia
- Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, 00146, Rome, Italy.
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14
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Li H, Zhang W, Liu Y, Cai Z, Lan A, Shu D, Shen M, Li K, Pu D, Tan W, Liu S, Peng Y. UTRN as a potential biomarker in breast cancer: a comprehensive bioinformatics and in vitro study. Sci Rep 2024; 14:7702. [PMID: 38565593 PMCID: PMC10987506 DOI: 10.1038/s41598-024-58124-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 03/26/2024] [Indexed: 04/04/2024] Open
Abstract
Utrophin (UTRN), known as a tumor suppressor, potentially regulates tumor development and the immune microenvironment. However, its impact on breast cancer's development and treatment remains unstudied. We conducted a thorough examination of UTRN using both bioinformatic and in vitro experiments in this study. We discovered UTRN expression decreased in breast cancer compared to standard samples. High UTRN expression correlated with better prognosis. Drug sensitivity tests and RT-qPCR assays revealed UTRN's pivotal role in tamoxifen resistance. Furthermore, the Kruskal-Wallis rank test indicated UTRN's potential as a valuable diagnostic biomarker for breast cancer and its utility in detecting T stage of breast cancer. Additionally, our results demonstrated UTRN's close association with immune cells, inhibitors, stimulators, receptors, and chemokines in breast cancer (BRCA). This research provides a novel perspective on UTRN's role in breast cancer's prognostic and therapeutic value. Low UTRN expression may contribute to tamoxifen resistance and a poor prognosis. Specifically, UTRN can improve clinical decision-making and raise the diagnosis accuracy of breast cancer.
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Affiliation(s)
- Han Li
- Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, China
| | - Wenjie Zhang
- Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, China
| | - Yang Liu
- Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, China
| | - Zehao Cai
- Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, China
| | - Ailin Lan
- Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, China
| | - Dan Shu
- Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, China
| | - Meiying Shen
- Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, China
| | - Kang Li
- Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, China
| | - Dongyao Pu
- Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, China
| | - Wenhao Tan
- Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, China
| | - Shengchun Liu
- Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, China
| | - Yang Peng
- Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, China.
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15
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Ho I, Wong CK, Wong YK, Lam TH, Sze-Him Leung I, Lin M, Tak-Wai Lui D, Kwok WC, Tam CC, Chan YH, Chan EW, Tse HF. Aromatase Inhibitor Therapy Increases the Risk of New-Onset Atrial Fibrillation in Patients With Breast Cancer. JACC. ASIA 2024; 4:150-160. [PMID: 38371283 PMCID: PMC10866735 DOI: 10.1016/j.jacasi.2023.09.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 09/19/2023] [Accepted: 09/20/2023] [Indexed: 02/20/2024]
Abstract
Background Previous studies suggest that aromatase inhibitors (AIs) increase the risk of adverse cardiovascular events and cardiac arrhythmias in patients with breast cancer, but it is unclear whether AIs also increase the risk of new-onset atrial fibrillation (AF). Objectives The purpose of this study was to investigate whether the use of AIs was associated with an increased risk of new-onset AF in patients with breast cancer. Methods We performed a retrospective analysis involving 5,707 patients with breast cancer (mean age 63.9 ± 11.2 years and 99.9% women) who received adjunctive hormone therapy with an AI (AI group, n = 4,878) or tamoxifen (tamoxifen group, n = 829) in Hong Kong between January 1, 1999, and December 31, 2020. After propensity score matching, there were 1,658 and 829 patients with balanced characteristics in the AI group and tamoxifen group, respectively. Results After 8,863 patient-years of follow-up, patients who were prescribed AI had a trend toward more new-onset arrhythmias compared with those prescribed tamoxifen (0.62 vs 0.30 per 100 patient-years; crude HR: 2.05; P = 0.053). The difference in arrhythmic risk was mainly driven by a higher incidence rate of new-onset AF in the AI group (0.59 vs 0.27 per 100 patient-years; crude HR: 2.18; P = 0.046). The use of AIs was confirmed to be an independent risk factor for new-onset AF on multivariate analysis (adjusted HR: 2.75; P = 0.01). Conclusions Among breast cancer patients prescribed adjunctive hormonal therapy, AI was associated with an increased risk of new-onset AF. Regular surveillance for new-onset AF should be considered in breast cancer patients treated with an AI.
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Affiliation(s)
- Isaac Ho
- Department of Clinical Oncology, Queen Mary Hospital, Hong Kong SAR
| | - Chun-Ka Wong
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR
| | - Yuen-Kwun Wong
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR
| | - Tsun-Ho Lam
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR
| | | | - Minqing Lin
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR
| | - David Tak-Wai Lui
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR
| | - Wang Chun Kwok
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR
| | - Chor-Cheung Tam
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR
| | - Yap-Hang Chan
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR
| | - Esther W.Y. Chan
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR
| | - Hung-Fat Tse
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR
- Cardiac and Vascular Center, Hong Kong University Shenzhen Hospital, Shenzhen, China
- Center for Translational Stem Cell Biology, Hong Kong SAR, China
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16
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Gadwal A, Purohit P, Khokhar M, Vishnoi JR, Pareek P, Choudhary R, Elhence P, Banerjee M, Sharma P. In silico analysis of differentially expressed-aberrantly methylated genes in breast cancer for prognostic and therapeutic targets. Clin Exp Med 2023; 23:3847-3866. [PMID: 37029310 DOI: 10.1007/s10238-023-01060-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 03/28/2023] [Indexed: 04/09/2023]
Abstract
Breast cancer (BC) is the leading cause of death among women across the globe. Abnormal gene expression plays a crucial role in tumour progression, carcinogenesis and metastasis of BC. The alteration of gene expression may be through aberrant gene methylation. In the present study, differentially expressed genes which may be regulated by DNA methylation and their pathways associated with BC have been identified. Expression microarray datasets GSE10780, GSE10797, GSE21422, GSE42568, GSE61304, GSE61724 and one DNA methylation profile dataset GSE20713 were downloaded from Gene Expression Omnibus database (GEO). Differentially expressed-aberrantly methylated genes were identified using online Venn diagram tool. Based on fold change expression of differentially expressed-aberrantly methylated genes were chosen through heat map. Protein-protein interaction (PPI) network of the hub genes was constructed by Search Tool for the Retrieval of Interacting Genes (STRING). Gene expression and DNA methylation level of the hub genes were validated through UALCAN. Overall survival analysis of the hub genes was analysed through Kaplan-Meier plotter database for BC. A total of 72 upregulated-hypomethylated genes and 92 downregulated-hypermethylated genes were obtained from GSE10780, GSE10797, GSE21422, GSE42568, GSE61304, GSE61724, and GSE20713 datasets by GEO2R and Venn diagram tool. PPI network of the upregulated-hypomethylated hub genes (MRGBP, MANF, ARF3, HIST1H3D, GSK3B, HJURP, GPSM2, MATN3, KDELR2, CEP55, GSPT1, COL11A1, and COL1A1) and downregulated-hypermethylated hub genes were constructed (APOD, DMD, RBPMS, NR3C2, HOXA9, AMKY2, KCTD9, and EDN1). All the differentially expressed hub genes expression was validated in UALCAN database. 4 in 13 upregulated-hypomethylated and 5 in 8 downregulated-hypermethylated hub genes to be significantly hypomethylated or hypermethylated in BC were confirmed using UALCAN database (p < 0.05). MANF, HIST1H3D, HJURP, GSK3B, GPSM2, MATN3, KDELR2, CEP55, COL1A1, APOD, RBPMS, NR3C2, HOXA9, ANKMY2, and EDN1 were significantly (p < 0.05) associated with poor overall survival (OS). The identified aberrantly methylated-differentially expressed genes and their related pathways and function in BC can serve as novel diagnostic and prognostic biomarkers and therapeutic targets.Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Author 4 Given name: [Jeewan Ram] Last name [Vishnoi]. Also, kindly confirm the details in the metadata are correct.It is correct.
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Affiliation(s)
- Ashita Gadwal
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Basni Industrial Area, MIA 2nd Phase, Basni, Jodhpur, Rajasthan, 342005, India
| | - Purvi Purohit
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Basni Industrial Area, MIA 2nd Phase, Basni, Jodhpur, Rajasthan, 342005, India.
| | - Manoj Khokhar
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Basni Industrial Area, MIA 2nd Phase, Basni, Jodhpur, Rajasthan, 342005, India
| | - Jeewan Ram Vishnoi
- Department of Oncosurgery, All India Institute of Medical Sciences, Jodhpur, Basni Industrial Area, MIA 2nd Phase, Basni, Jodhpur, Rajasthan, 342005, India
| | - Puneet Pareek
- Department of Radiation Oncology, All India Institute of Medical Sciences, Jodhpur, Basni Industrial Area, MIA 2nd Phase, Basni, Jodhpur, Rajasthan, 342005, India
| | - Ramkaran Choudhary
- Department of General Surgery, All India Institute of Medical Sciences, Jodhpur, Basni Industrial Area, MIA 2nd Phase, Basni, Jodhpur, Rajasthan, 342005, India
| | - Poonam Elhence
- Department of Pathology, All India Institute of Medical Sciences, Jodhpur, Basni Industrial Area, MIA 2nd Phase, Basni, Jodhpur, Rajasthan, 342005, India
| | - Mithu Banerjee
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Basni Industrial Area, MIA 2nd Phase, Basni, Jodhpur, Rajasthan, 342005, India
| | - Praveen Sharma
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Basni Industrial Area, MIA 2nd Phase, Basni, Jodhpur, Rajasthan, 342005, India
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17
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Etrusco A, Barra F, Chiantera V, Ferrero S, Bogliolo S, Evangelisti G, Oral E, Pastore M, Izzotti A, Venezia R, Ceccaroni M, Laganà AS. Current Medical Therapy for Adenomyosis: From Bench to Bedside. Drugs 2023; 83:1595-1611. [PMID: 37837497 PMCID: PMC10693526 DOI: 10.1007/s40265-023-01957-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/28/2023] [Indexed: 10/16/2023]
Abstract
Adenomyosis, characterized by the growth of endometrial tissue within the uterine wall, poses significant challenges in treatment. The literature primarily focuses on managing abnormal uterine bleeding (AUB) and dysmenorrhea, the main symptoms of adenomyosis. Nonsteroidal anti-inflammatory drugs (NSAIDs) and tranexamic acid provide limited support for mild symptoms or symptom re-exacerbation during hormone therapy. The levonorgestrel-releasing intrauterine system (LNG-IUS) is commonly employed in adenomyosis management, showing promise in symptom improvement and reducing uterine size, despite the lack of standardized guidelines. Dienogest (DNG) also exhibits potential benefits, but limited evidence hinders treatment recommendations. Danazol, while effective, is limited by androgenic side effects. Combined oral contraceptives (COCs) may be less effective than progestins but can be considered for contraception in young patients. Gonadotropin-releasing hormone (GnRH) agonists effectively manage symptoms but induce menopausal symptoms with prolonged use. GnRH antagonists are a recent option requiring further investigation. Aromatase inhibitors (AIs) show promise in alleviating AUB and pelvic pain, but their safety necessitates exploration and limited use within trials for refractory patients. This review highlights the complexity of diagnosing adenomyosis, its coexistence with endometriosis and uterine leiomyomas, and its impact on fertility and quality of life, complicating treatment decisions. It emphasizes the need for research on guidelines for medical management, fertility outcomes, long-term effects of therapies, and exploration of new investigational targets. Future research should optimize therapeutic strategies, expand our understanding of adenomyosis and its management, and establish evidence-based guidelines to improve patient outcomes and quality of life.
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Affiliation(s)
- Andrea Etrusco
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
- Unit of Obstetrics and Gynecology, "Paolo Giaccone" Hospital, Palermo, Italy
| | - Fabio Barra
- Unit of Obstetrics and Gynecology, P.O. "Ospedale del Tigullio"-ASL4, Metropolitan Area of Genoa, Genoa, Italy.
- Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy.
| | - Vito Chiantera
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
- Unit of Gynecologic Oncology, National Cancer Institute-IRCCS-Fondazione "G. Pascale", Naples, Italy
| | - Simone Ferrero
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy
- Academic Unit of Obstetrics and Gynecology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Stefano Bogliolo
- Unit of Obstetrics and Gynecology, P.O. "Ospedale del Tigullio"-ASL4, Metropolitan Area of Genoa, Genoa, Italy
| | - Giulio Evangelisti
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy
| | - Engin Oral
- Department of Obstetrics and Gynecology, Bezmialem Vakif University, Istanbul, Turkey
| | - Mariana Pastore
- Hospital Pharmacy, Santa Maria della Misericordia University Hospital, University of Udine, Udine, Italy
| | - Alberto Izzotti
- Unit of Mutagenesis and Cancer Prevention, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy
| | - Renato Venezia
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
- Unit of Obstetrics and Gynecology, "Paolo Giaccone" Hospital, Palermo, Italy
| | - Marcello Ceccaroni
- Department of Obstetrics and Gynecology, Gynecologic Oncology and Minimally Invasive Pelvic Surgery, International School of Surgical Anatomy, IRCCS "Sacro Cuore-Don Calabria" Hospital, Negrar di Valpolicella, Verona, Italy
| | - Antonio Simone Laganà
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
- Unit of Obstetrics and Gynecology, "Paolo Giaccone" Hospital, Palermo, Italy
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18
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Mesa D, Augusto YE, Hernández G, Figueroa-Macías JP, Coll F, Olea AF, Núñez M, Campo HA, Coll Y, Espinoza L. The Synthesis of Novel aza-Steroids and α, β-Unsaturated-Cyanoketone from Diosgenin. Molecules 2023; 28:7283. [PMID: 37959702 PMCID: PMC10649921 DOI: 10.3390/molecules28217283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 10/15/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
Recent studies have demonstrated the antiproliferative and cytotoxic effects of aza-steroids and steroidal sapogenins on human cancer cell lines. The scientific community has shown a growing interest in these compounds as drug candidates for cancer treatment. In the current work, we report the synthesis of new diosgenin oxime derivatives as potential antiproliferative agents. From (25 R)-5α-spirost-3,5,6-triol (1), a diosgenin derivative, ketones 2, 3, 4, and 9 were obtained and used as precursors of the new oximes. A condensation reaction was carried out between the steroidal ketones (2, 3, 4, and 9) with hydroxylamine hydrochloride in 2,4,6-trimethylpyridine to produce five spirostanic oximes (four of them are not reported before) with a 42-96% yield. Also, a new spirostanic α, β-unsaturated cyanoketone was synthesized via Beckmann fragmentation using thionyl chloride with a 62% yield. Furthermore, we proposed a reaction mechanism with the aim of explaining such transformation.
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Affiliation(s)
- Dayana Mesa
- Center for Natural Product Researches, Faculty of Chemistry, University of Havana, Zapata and G, Vedado, Havana 10400, Cuba; (D.M.); (Y.E.A.); (G.H.); (J.P.F.-M.); (F.C.)
| | - Yarelys E. Augusto
- Center for Natural Product Researches, Faculty of Chemistry, University of Havana, Zapata and G, Vedado, Havana 10400, Cuba; (D.M.); (Y.E.A.); (G.H.); (J.P.F.-M.); (F.C.)
| | - Giselle Hernández
- Center for Natural Product Researches, Faculty of Chemistry, University of Havana, Zapata and G, Vedado, Havana 10400, Cuba; (D.M.); (Y.E.A.); (G.H.); (J.P.F.-M.); (F.C.)
| | - Juan P. Figueroa-Macías
- Center for Natural Product Researches, Faculty of Chemistry, University of Havana, Zapata and G, Vedado, Havana 10400, Cuba; (D.M.); (Y.E.A.); (G.H.); (J.P.F.-M.); (F.C.)
| | - Francisco Coll
- Center for Natural Product Researches, Faculty of Chemistry, University of Havana, Zapata and G, Vedado, Havana 10400, Cuba; (D.M.); (Y.E.A.); (G.H.); (J.P.F.-M.); (F.C.)
| | - Andrés F. Olea
- Grupo QBAB, Facultad de Ingeniería, Instituto de Ciencias Químicas Aplicadas, Universidad Autónoma de Chile, Llano Subercaseaux 2801, Santiago 7500912, Chile;
| | - María Núñez
- Departamento de Química, Universidad Técnica Federico Santa María, Av. España No. 1680, Valparaíso 2390123, Chile;
| | - Hernán Astudillo Campo
- Grupo de Investigación en Procesos Electroquímicos, Departamento de Química, Universidad del Cauca, Calle 5 No. 4-70, Popayán 190003, Colombia
| | - Yamilet Coll
- Center for Natural Product Researches, Faculty of Chemistry, University of Havana, Zapata and G, Vedado, Havana 10400, Cuba; (D.M.); (Y.E.A.); (G.H.); (J.P.F.-M.); (F.C.)
| | - Luis Espinoza
- Departamento de Química, Universidad Técnica Federico Santa María, Av. España No. 1680, Valparaíso 2390123, Chile;
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19
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Jiang S, Meng Q, Ji F, Yin Y, Liu X, Shi W, Lyu Y. A bibliometric analysis of metastatic breast cancer: two-decade report (2002-2022). Front Oncol 2023; 13:1229222. [PMID: 37692861 PMCID: PMC10484517 DOI: 10.3389/fonc.2023.1229222] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 08/09/2023] [Indexed: 09/12/2023] Open
Abstract
Background MBC is a lethal form of breast cancer that arises when cancer cells invade other organs or tissues. The treatment of MBC needs personalized approaches based on the tumor and patient characteristics. The purpose of this paper is to analyze MBC studies from 2002 to 2022 using bibliometrics and to investigate its current situation, main contributors, core journals, highly cited papers, and topic evolution. Materials and methods We retrieved data from Web of Science Core Collection (WOSCC). Bibliometric analysis of the included literatures mainly used the following tools: the function of "analyze results" and "citation report" in WoS, Microsoft excel 2021, CiteSpace v.6.1. R6, VOSviewer v.1.6.18, BICOMB v.2.04 and gCLUTO v.1.0. Results We found 12,653 articles on MBC research published in 1, 802 journals by 69, 753 authors from 118 countries. The annual output and citation of MBC articles showed a rising trend over time. The United States was the most influential country in MBC research. The most cited journal in this field was The Journal of Clinical Oncology. And the most cited article was by Slamon DJ. The co-word analysis of keywords divides MBC into six research clusters. The hormone receptor-positive MBC and liquid biopsy of MBC are the frontiers research trends. "CDK4/6 inhibitor" had the highest burst strength. Conclusion Our bibliometric analysis offers a comprehensive overview of MBC research in the past two decades. It shows the current situation, main contributors, core journals, highly cited papers, and topic evolution of this field. Our study can assist researchers and practitioners to comprehend the development and trends of MBC research and to discover potential directions for future research.
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Affiliation(s)
- Siyuan Jiang
- Department of Thyroid Breast Surgery, Xi’an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, Shaanxi, China
| | - Qingjie Meng
- Department of Thyroid Breast Surgery, Xi’an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, Shaanxi, China
| | - Fuqing Ji
- Department of Thyroid Breast Surgery, Xi’an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, Shaanxi, China
| | - Yulong Yin
- Department of Thyroid Breast Surgery, Xi’an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, Shaanxi, China
| | - Xianghua Liu
- Department of Thyroid Breast Surgery, Xi’an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, Shaanxi, China
| | - Wenzhen Shi
- Clinical Medical Research Center, the Affiliated Hospital of Northwest University, Xi’an No.3 Hospital, Xi’an, Shaanxi, China
- Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, the Affiliated Hospital of Northwest University, Xi’an No.3 Hospital, Xi’an, Shaanxi, China
| | - Yonggang Lyu
- Department of Thyroid Breast Surgery, Xi’an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, Shaanxi, China
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20
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Talia M, Cirillo F, Spinelli A, Zicarelli A, Scordamaglia D, Muglia L, De Rosis S, Rigiracciolo DC, Filippelli G, Perrotta ID, Davoli M, De Rosa R, Macirella R, Brunelli E, Miglietta AM, Nardo B, Tosoni D, Pece S, De Francesco EM, Belfiore A, Maggiolini M, Lappano R. The Ephrin tyrosine kinase a3 (EphA3) is a novel mediator of RAGE-prompted motility of breast cancer cells. J Exp Clin Cancer Res 2023; 42:164. [PMID: 37434266 DOI: 10.1186/s13046-023-02747-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 07/03/2023] [Indexed: 07/13/2023] Open
Abstract
BACKGROUND The receptor for advanced glycation-end products (RAGE) and its ligands have been implicated in obesity and associated inflammatory processes as well as in metabolic alterations like diabetes. In addition, RAGE-mediated signaling has been reported to contribute to the metastatic progression of breast cancer (BC), although mechanistic insights are still required. Here, we provide novel findings regarding the transcriptomic landscape and the molecular events through which RAGE may prompt aggressive features in estrogen receptor (ER)-positive BC. METHODS MCF7 and T47D BC cells stably overexpressing human RAGE were used as a model system to evaluate important changes like cell protrusions, migration, invasion and colony formation both in vitro through scanning electron microscopy, clonogenic, migration and invasion assays and in vivo through zebrafish xenografts experiments. The whole transcriptome of RAGE-overexpressing BC cells was screened by high-throughput RNA sequencing. Thereafter, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses allowed the prediction of potential functions of differentially expressed genes (DEGs). Flow cytometry, real time-PCR, chromatin immunoprecipitation, immunofluorescence and western blot assays were performed to investigate the molecular network involved in the regulation of a novel RAGE target gene namely EphA3. The clinical significance of EphA3 was explored in the TCGA cohort of patients through the survivALL package, whereas the pro-migratory role of EphA3 signaling was ascertained in both BC cells and cancer-associated fibroblasts (CAFs). Statistical analysis was performed by t-tests. RESULTS RNA-seq findings and GSEA analysis revealed that RAGE overexpression leads to a motility-related gene signature in ER-positive BC cells. Accordingly, we found that RAGE-overexpressing BC cells exhibit long filopodia-like membrane protrusions as well as an enhanced dissemination potential, as determined by the diverse experimental assays. Mechanistically, we established for the first time that EphA3 signaling may act as a physical mediator of BC cells and CAFs motility through both homotypic and heterotypic interactions. CONCLUSIONS Our data demonstrate that RAGE up-regulation leads to migratory ability in ER-positive BC cells. Noteworthy, our findings suggest that EphA3 may be considered as a novel RAGE target gene facilitating BC invasion and scattering from the primary tumor mass. Overall, the current results may provide useful insights for more comprehensive therapeutic approaches in BC, particularly in obese and diabetic patients that are characterized by high RAGE levels.
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Affiliation(s)
- Marianna Talia
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy
| | - Francesca Cirillo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy
| | - Asia Spinelli
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy
| | - Azzurra Zicarelli
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy
| | - Domenica Scordamaglia
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy
| | - Lucia Muglia
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy
| | - Salvatore De Rosis
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy
| | | | | | - Ida Daniela Perrotta
- Department of Biology, Ecology and Earth Science, University of Calabria, 87036, Rende, Italy
| | - Mariano Davoli
- Department of Biology, Ecology and Earth Science, University of Calabria, 87036, Rende, Italy
| | - Rosanna De Rosa
- Department of Biology, Ecology and Earth Science, University of Calabria, 87036, Rende, Italy
| | - Rachele Macirella
- Department of Biology, Ecology and Earth Science, University of Calabria, 87036, Rende, Italy
| | - Elvira Brunelli
- Department of Biology, Ecology and Earth Science, University of Calabria, 87036, Rende, Italy
| | - Anna Maria Miglietta
- Breast and General Surgery Unit, Regional Hospital Cosenza, 87100, Cosenza, Italy
| | - Bruno Nardo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy
- Breast and General Surgery Unit, Regional Hospital Cosenza, 87100, Cosenza, Italy
| | - Daniela Tosoni
- European Institute of Oncology IRCCS, Via Ripamonti 435, 20141, Milan, Italy
| | - Salvatore Pece
- European Institute of Oncology IRCCS, Via Ripamonti 435, 20141, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università Degli Studi Di Milano, 20142, Milan, Italy
| | - Ernestina Marianna De Francesco
- Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, 95122, Italy
| | - Antonino Belfiore
- Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, 95122, Italy
| | - Marcello Maggiolini
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy.
| | - Rosamaria Lappano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy.
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21
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Aalhate M, Mahajan S, Singh H, Guru SK, Singh PK. Nanomedicine in therapeutic warfront against estrogen receptor-positive breast cancer. Drug Deliv Transl Res 2023; 13:1621-1653. [PMID: 36795198 DOI: 10.1007/s13346-023-01299-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/06/2023] [Indexed: 02/17/2023]
Abstract
Breast cancer (BC) is the most frequently diagnosed malignancy in women worldwide. Almost 70-80% of cases of BC are curable at the early non-metastatic stage. BC is a heterogeneous disease with different molecular subtypes. Around 70% of breast tumors exhibit estrogen-receptor (ER) expression and endocrine therapy is used for the treatment of these patients. However, there are high chances of recurrence in the endocrine therapy regimen. Though chemotherapy and radiation therapy have substantially improved survival rates and treatment outcomes in BC patients, there is an increased possibility of the development of resistance and dose-limiting toxicities. Conventional treatment approaches often suffer from low bioavailability, adverse effects due to the non-specific action of chemotherapeutics, and low antitumor efficacy. Nanomedicine has emerged as a conspicuous strategy for delivering anticancer therapeutics in BC management. It has revolutionized the area of cancer therapy by increasing the bioavailability of the therapeutics and improving their anticancer efficacy with reduced toxicities on healthy tissues. In this article, we have highlighted various mechanisms and pathways involved in the progression of ER-positive BC. Further, different nanocarriers delivering drugs, genes, and natural therapeutic agents for surmounting BC are the spotlights of this article.
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Affiliation(s)
- Mayur Aalhate
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Srushti Mahajan
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Hoshiyar Singh
- Department of Biological Science, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India
| | - Santosh Kumar Guru
- Department of Biological Science, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India
| | - Pankaj Kumar Singh
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India.
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22
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Shanmugarajan D, Biju A, Sibi D, Sibi R, Shaji M, David C. Dynamacophore model for breast cancer estrogen receptor alpha as an effective lead generation screening technique. J Biomol Struct Dyn 2023; 41:13029-13040. [PMID: 37154819 DOI: 10.1080/07391102.2023.2203245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 01/11/2023] [Indexed: 05/10/2023]
Abstract
Regardless to overwhelming quantum of cancer research worldwide, there are few drugs on the market to treat disease conditions. This is owing to multiple process inferences of drug targets in integrated pathways for invasion, growth, and metastasis. Over the past years, the death rate due to breast cancer has been increasing, that set the stage for improved better treatment. Therefore, there is a persistent and vital demand for innovative development of drugs to treat breast cancer. Many studies have reported that more than 60% of breast cancers are Estrogen receptor-α (ERα)-positive tumours and a key transcription factor, Estrogen receptor-α (ERα) was believed to promote proliferation of breast cancer cells. In this study, 150 ns of molecular dynamics was performed for protein-ligand complex to retrieve the potential stable conformations. The most populated dynamics cluster of 4-Hydroxytamoxifen intact with active site amino acid was selected to generate dynamacophore model (dynamic pharmacophore). Further, internal model validation with AU-ROC values ∼0.93 indicate the best model to screen library. The refined hits are funnelled in pharmacokinetics/dynamics, CDOCKER molecular docking, MM-GBSA and density functional theory to identify the promising ERα ligand candidates.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Dhivya Shanmugarajan
- Department of Biotechnology, Vignan's Foundation for Science, Technology and Research (Deemed to be University), Guntur, Andhra Pradesh, India
| | - Anagha Biju
- Department of Biotechnology, Vignan's Foundation for Science, Technology and Research (Deemed to be University), Guntur, Andhra Pradesh, India
| | - Dona Sibi
- Department of Biotechnology, Vignan's Foundation for Science, Technology and Research (Deemed to be University), Guntur, Andhra Pradesh, India
| | - Rona Sibi
- Department of Biotechnology, Vignan's Foundation for Science, Technology and Research (Deemed to be University), Guntur, Andhra Pradesh, India
| | - Maria Shaji
- Department of Biotechnology, Vignan's Foundation for Science, Technology and Research (Deemed to be University), Guntur, Andhra Pradesh, India
| | - Charles David
- Department of Biotechnology, Vignan's Foundation for Science, Technology and Research (Deemed to be University), Guntur, Andhra Pradesh, India
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23
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Bhatia N, Hazra S, Thareja S. Selective Estrogen receptor degraders (SERDs) for the treatment of breast cancer: An overview. Eur J Med Chem 2023; 256:115422. [PMID: 37163948 DOI: 10.1016/j.ejmech.2023.115422] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/17/2023] [Accepted: 04/26/2023] [Indexed: 05/12/2023]
Abstract
Discovery of SERDs has changed the direction of anticancer research, as more than 70% of breast cancer cases are estrogen receptor positive (ER+). Therapies such as selective estrogen receptor modulators (SERM) and aromatase inhibitors (AI's) have been effective, but due to endocrine resistance, SERDs are now considered essential therapeutics for the treatment of ER+ breast cancer. The present review deliberates the pathophysiology of SERDs from the literature covering various molecules in clinical trials. Estrogen receptors active sites distinguishing characteristics and interactions with currently available FDA-approved drugs have also been discussed. Designing strategy of previously reported SERDs, their SAR analysis, in silico, and the biological efficacy have also been summarized along with appropriate examples.
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Affiliation(s)
- Neha Bhatia
- Department of Pharmaceutical Sciences and Natural Products, School of Pharmaceutical Sciences, Central University of Punjab, Bathinda, Punjab, 151401, India
| | - Shreejita Hazra
- Department of Pharmaceutical Sciences and Natural Products, School of Pharmaceutical Sciences, Central University of Punjab, Bathinda, Punjab, 151401, India
| | - Suresh Thareja
- Department of Pharmaceutical Sciences and Natural Products, School of Pharmaceutical Sciences, Central University of Punjab, Bathinda, Punjab, 151401, India.
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24
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Pérez-Bilbao T, Alonso-Dueñas M, Peinado AB, San Juan AF. Effects of Combined Interventions of Exercise and Diet or Exercise and Supplementation on Breast Cancer Patients: A Systematic Review. Nutrients 2023; 15:nu15041013. [PMID: 36839371 PMCID: PMC9964362 DOI: 10.3390/nu15041013] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 01/25/2023] [Accepted: 02/15/2023] [Indexed: 02/22/2023] Open
Abstract
This systematic review investigated the effects of exercise interventions combined with diet and/or dietary supplement interventions on anthropometry, body composition, metabolic biomarkers, physical function, healthy lifestyles, quality of life, psychosocial variables and fatigue for women with breast cancer. A systematic search was performed in the PubMed and Web of Science databases (from inception to 1 March 2022). A review was carried out following the Preferred Reporting Items for Systematic review and Meta-Analyses (PRISMA) guidelines. The methodological quality and the risk of bias of the included studies was assessed with the Physiotherapy Evidence Database (PEDro) scale. A total of 13 randomised controlled trial studies were included, comprising 1569 breast cancer patients. The main finding of this systematic review is that groups performing interventions combining exercise plus diet show significant improvements in cardiorespiratory fitness, muscular strength, body composition, quality of life, fatigue, anxiety, depression and sleep compared to control groups. On the other hand, the use of interventions combining exercise plus supplementation does not result in an improvement compared to groups using exercise alone or supplementation alone.
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Affiliation(s)
- Txomin Pérez-Bilbao
- Department of Health and Human Performance, Faculty of Physical Activity and Sports Sciences (INEF), Universidad Politécnica de Madrid, 28040 Madrid, Spain
| | - María Alonso-Dueñas
- Department of Health and Human Performance, Faculty of Physical Activity and Sports Sciences (INEF), Universidad Politécnica de Madrid, 28040 Madrid, Spain
- GEICAM Spanish Breast Cancer Group, 28703 Madrid, Spain
| | - Ana B. Peinado
- Department of Health and Human Performance, Faculty of Physical Activity and Sports Sciences (INEF), Universidad Politécnica de Madrid, 28040 Madrid, Spain
- LFE Research Group, Universidad Politécnica de Madrid, 28040 Madrid, Spain
| | - Alejandro F. San Juan
- Department of Health and Human Performance, Faculty of Physical Activity and Sports Sciences (INEF), Universidad Politécnica de Madrid, 28040 Madrid, Spain
- Correspondence:
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25
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Yang F, He Q, Dai X, Zhang X, Song D. The potential role of nanomedicine in the treatment of breast cancer to overcome the obstacles of current therapies. Front Pharmacol 2023; 14:1143102. [PMID: 36909177 PMCID: PMC9992554 DOI: 10.3389/fphar.2023.1143102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 02/13/2023] [Indexed: 02/24/2023] Open
Abstract
Breast cancer (BC) is the most frequently diagnosed malignant tumor among women in the world. BC is the heterogeneous tumor with different subtypes including luminal A-like, luminal B-like (HER2-/HER2+), HER2 enriched, and triple-negative BC. The therapeutic strategies including surgery, chemotherapy, radiotherapy, targeted therapy, and endocrine therapy are well developed and commonly used in the treatment of BC. However, some adverse effects of these conventional treatments limited their wide application in clinical. Therefore, it is necessary to develop more safe and more efficient individualized treatment strategies of the BC. Nanomedicine, as the most promising strategy for controlled and targeted drug delivery, is widely used in multiple aspects of cancer therapy. Importantly, accumulative evidences show that nanomedicine has achieved good outcomes in the treatment of BC and a huge amount of BC patients benefited from the nanomedicine related treatments. In this review, we summarized and discussed the major problems occurred during the administration of conventional treatment strategies for BC and the potential roles of nanomedicine in promoting the treatment efficacy of BC by overcoming obstacles of current treatment of BC.
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Affiliation(s)
- Fan Yang
- Breast Surgery Department of General Surgery, The First Hospital of Jilin University, Changchun, China.,Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital of Jilin University, Changchun, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital of Jilin University, Changchun, China
| | - Qingjie He
- Breast Surgery Department of General Surgery, The First Hospital of Jilin University, Changchun, China.,Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital of Jilin University, Changchun, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital of Jilin University, Changchun, China
| | - Xiangpeng Dai
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital of Jilin University, Changchun, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital of Jilin University, Changchun, China
| | - Xiaoling Zhang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital of Jilin University, Changchun, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital of Jilin University, Changchun, China
| | - Dong Song
- Breast Surgery Department of General Surgery, The First Hospital of Jilin University, Changchun, China
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26
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Cipolletti M, Leone S, Bartoloni S, Acconcia F. A functional genetic screen for metabolic proteins unveils GART and the de novo purine biosynthetic pathway as novel targets for the treatment of luminal A ERα expressing primary and metastatic invasive ductal carcinoma. Front Endocrinol (Lausanne) 2023; 14:1129162. [PMID: 37143728 PMCID: PMC10151738 DOI: 10.3389/fendo.2023.1129162] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 03/31/2023] [Indexed: 05/06/2023] Open
Abstract
Targeting tumor cell metabolism is a new frontier in cancer management. Thus, metabolic pathway inhibitors could be used as anti-estrogen receptor α (ERα) breast cancer (BC) drugs. Here, the interplay among metabolic enzyme(s), the ERα levels and cell proliferation was studied. siRNA-based screen directed against different metabolic proteins in MCF10a, MCF-7 and MCF-7 cells genetically resistant to endocrine therapy (ET) drugs and metabolomic analyses in numerous BC cell lines unveil that the inhibition of GART, a key enzyme in the purine de novo biosynthetic pathway, induces ERα degradation and prevent BC cell proliferation. We report here that a reduced GART expression correlates with a longer relapse-free-survival (RFS) in women with ERα-positive BCs. ERα-expressing luminal A invasive ductal carcinomas (IDCs) are sensitive to GART inhibition and GART expression is increased in receptor-positive IDCs of high grade and stage and plays a role in the development of ET resistance. Accordingly, GART inhibition reduces ERα stability and cell proliferation in IDC luminal A cells where it deregulates 17β-estradiol (E2):ERα signaling to cell proliferation. Moreover, the GART inhibitor lometrexol (LMX) and drugs approved for clinical treatment of primary and metastatic BC (4OH-tamoxifen and the CDK4/CDK6 inhibitors) exert synergic antiproliferative effects in BC cells. In conclusion, GART inhibition by LMX or other inhibitors of the de novo purine biosynthetic pathway could be a novel effective strategy for the treatment of primary and metastatic BCs.
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27
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Expression and Signaling Pathways of Nerve Growth Factor (NGF) and Pro-NGF in Breast Cancer: A Systematic Review. Curr Oncol 2022; 29:8103-8120. [PMID: 36354700 PMCID: PMC9689427 DOI: 10.3390/curroncol29110640] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/19/2022] [Accepted: 10/25/2022] [Indexed: 11/07/2022] Open
Abstract
Breast cancer represents the most common type of cancer and is the leading cause of death due to cancer among women. Thus, the prevention and early diagnosis of breast cancer is of primary urgency, as well as the development of new treatments able to improve its prognosis. Nerve Growth Factor (NGF) is a neurotrophic factor involved in the regulation of neuronal functions through the binding of the Tropomyosin receptor kinase A (TrkA) and the Nerve Growth Factor receptor or Pan-Neurotrophin Receptor 75 (NGFR/p75NTR). In addition, its precursor (pro-NGF) can extert biological activity by forming a trimeric complex with NGFR/p75NTR and sortilin, or by binding to TrkA receptors with low affinity. Several examples of in vitro and in vivo evidence show that NGF is both synthesized and released by breast cancer cells, and has mitogen, antiapoptotic and angiogenic effects on these cells through the activation of different signaling cascades that involve TrkA and NGFR/p75NTR receptors. Conversely, pro-NGF signaling has been related to breast cancer invasion and metastasis. Other studies suggested that NGF and its receptors could represent a good diagnostic and prognostic tool, as well as promising therapeutic targets for breast cancer. In this paper, we comprehensively summarize and systematically review the current experimental evidence on this topic. INPLASY ID: INPLASY2022100017.
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28
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Acconcia F. Evaluation of the Sensitivity of Breast Cancer Cell Lines to Cardiac Glycosides Unveils ATP1B3 as a Possible Biomarker for the Personalized Treatment of ERα Expressing Breast Cancers. Int J Mol Sci 2022; 23:ijms231911102. [PMID: 36232400 PMCID: PMC9569938 DOI: 10.3390/ijms231911102] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/17/2022] [Accepted: 09/18/2022] [Indexed: 11/30/2022] Open
Abstract
The molecular classification of breast cancer (BC) dictates pharmacological treatment. Estrogen receptor α (ERα) expressing tumors are treated with 4OH-tamoxifen or fulvestrant, which inhibits the receptor, or with aromatase inhibitors (i.e., anastrozole, letrozole, and exemestane) that reduce the 17β-estradiol (E2) circulating blood levels. Besides such endocrine therapy (ET) drugs, ERα-positive BCs can be treated with epidermal growth factor receptor (EGF-R) inhibitors (i.e., gefitinib, erlotinib, and lapatinib) according to HER2 expression. Notwithstanding these anti-BC drugs, novel personalized approaches for BC treatment are required because prolonged administration of those pharmaceutics determines resistant phenotypes, which result in metastatic BC. We have recently reported that the cardiac glycoside (CG) (i.e., Na/K ATPase inhibitor) ouabain could be repurposed for ERα-positive primary and metastatic BC treatment as it induces ERα degradation and kills BC cells. Here, we evaluated if other CGs could represent additional treatment options for ERα-positive BCs and if the Na/K ATPase could be considered a biomarker for ERα-positive BC treatment. The results indicate that the ATP1B3 Na/K ATPase isoform can educate the choice for the personalized treatment of ERα-positive BC with CGs and that CGs could be more efficacious if they are administered in association with gefitinib.
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Affiliation(s)
- Filippo Acconcia
- Department of Sciences, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146 Rome, Italy
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29
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Jia Y, Chen S, Wang C, Sun T, Yang L. Hyaluronic acid-based nano drug delivery systems for breast cancer treatment: Recent advances. Front Bioeng Biotechnol 2022; 10:990145. [PMID: 36091467 PMCID: PMC9449492 DOI: 10.3389/fbioe.2022.990145] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 08/05/2022] [Indexed: 11/13/2022] Open
Abstract
Breast cancer (BC) is the most common malignancy among females worldwide, and high resistance to drugs and metastasis rates are the leading causes of death in BC patients. Releasing anti-cancer drugs precisely to the tumor site can improve the efficacy and reduce the side effects on the body. Natural polymers are attracting extensive interest as drug carriers in treating breast cancer. Hyaluronic acid (HA) is a natural polysaccharide with excellent biocompatibility, biodegradability, and non-immunogenicity and is a significant component of the extracellular matrix. The CD44 receptor of HA is overexpressed in breast cancer cells and can be targeted to breast tumors. Therefore, many researchers have developed nano drug delivery systems (NDDS) based on the CD44 receptor tumor-targeting properties of HA. This review examines the application of HA in NDDSs for breast cancer in recent years. Based on the structural composition of NDDSs, they are divided into HA NDDSs, Modified HA NDDSs, and HA hybrid NDDSs.
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Affiliation(s)
- Yufeng Jia
- Department of Breast Medicine, Liaoning Cancer Hospital, Cancer Hospital of China Medical University, Shenyang, China
| | - Siwen Chen
- Center for Molecular Science and Engineering, College of Science, Northeastern University, Shenyang, China
- NHC Key Laboratory of Reproductive Health and Medical Genetics (China Medical University), Liaoning Research Institute of Family Planning (The Reproductive Hospital of China Medical University), Shenyang, China
| | - Chenyu Wang
- Department of Information Management, Cancer Hospital of China Medical University, Liaoning Cancer Hospital, Shenyang, China
| | - Tao Sun
- Department of Breast Medicine, Liaoning Cancer Hospital, Cancer Hospital of China Medical University, Shenyang, China
- *Correspondence: Tao Sun, ; Liqun Yang,
| | - Liqun Yang
- NHC Key Laboratory of Reproductive Health and Medical Genetics (China Medical University), Liaoning Research Institute of Family Planning (The Reproductive Hospital of China Medical University), Shenyang, China
- *Correspondence: Tao Sun, ; Liqun Yang,
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Bartoloni S, Leone S, Pescatori S, Cipolletti M, Acconcia F. The antiviral drug telaprevir induces cell death by reducing
FOXA1
expression in estrogen receptor α (
ERα
)‐positive breast cancer cells. Mol Oncol 2022; 16:3568-3584. [PMID: 36056637 PMCID: PMC9533686 DOI: 10.1002/1878-0261.13303] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 07/26/2022] [Accepted: 08/08/2022] [Indexed: 11/20/2022] Open
Abstract
Previously, we found that telaprevir (Tel), the inhibitor of hepatitis C virus NS3/4A serine protease, reduces estrogen receptor α (ERα) content at the transcriptional level without binding to the receptor, prevents ERα transcriptional activity, and inhibits basal and 17β‐estradiol (E2)‐dependent cell proliferation in different breast cancer (BC) cell lines. Here, we further characterize the Tel action mechanisms on ERα levels and function, identify a possible molecular target of Tel in BC cells, and evaluate Tel as an antiproliferative agent for BC treatment. Tel‐dependent reduction in ERα levels and function depends on a Tel‐dependent decrease in FOXA1 levels and activity. The effect of Tel is transduced by the IGF1‐R/AKT/FOXA1 pathway, with the antiviral compound interacting with IGF1‐R. Tel prevents the proliferation of several BC cell lines, while it does not affect the proliferation of normal nontransformed cell lines, and its antiproliferative effect is correlated with the ratio of FOXA1/IGF1‐R expression. In conclusion, Tel interferes with the IGF1‐R/AKT/FOXA1 pathway and induces cell death in ERα‐expressing BC cells. Thus, we propose that this antiviral could be repurposed for the treatment of ERα‐expressing BC.
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Affiliation(s)
- Stefania Bartoloni
- Department of Sciences, Section Biomedical Sciences and Technology University Roma TRE, Viale Guglielmo Marconi, 446 I‐00146 Rome Italy
| | - Stefano Leone
- Department of Sciences, Section Biomedical Sciences and Technology University Roma TRE, Viale Guglielmo Marconi, 446 I‐00146 Rome Italy
| | - Sara Pescatori
- Department of Sciences, Section Biomedical Sciences and Technology University Roma TRE, Viale Guglielmo Marconi, 446 I‐00146 Rome Italy
| | - Manuela Cipolletti
- Department of Sciences, Section Biomedical Sciences and Technology University Roma TRE, Viale Guglielmo Marconi, 446 I‐00146 Rome Italy
| | - Filippo Acconcia
- Department of Sciences, Section Biomedical Sciences and Technology University Roma TRE, Viale Guglielmo Marconi, 446 I‐00146 Rome Italy
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LIU J, LEUNG CT, LIANG L, WANG Y, CHEN J, LAI KP, TSE WKF. Deubiquitinases in Cancers: Aspects of Proliferation, Metastasis, and Apoptosis. Cancers (Basel) 2022; 14:cancers14143547. [PMID: 35884607 PMCID: PMC9323628 DOI: 10.3390/cancers14143547] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 07/13/2022] [Accepted: 07/18/2022] [Indexed: 12/24/2022] Open
Abstract
Simple Summary This review summarizes the current DUBs findings that correlate with the most common cancers in the world (liver, breast, prostate, colorectal, pancreatic, and lung cancers). The DUBs were further classified by their biological functions in terms of proliferation, metastasis, and apoptosis. The work provides an updated of the current findings, and could be used as a quick guide for researchers to identify target DUBs in cancers. Abstract Deubiquitinases (DUBs) deconjugate ubiquitin (UBQ) from ubiquitylated substrates to regulate its activity and stability. They are involved in several cellular functions. In addition to the general biological regulation of normal cells, studies have demonstrated their critical roles in various cancers. In this review, we evaluated and grouped the biological roles of DUBs, including proliferation, metastasis, and apoptosis, in the most common cancers in the world (liver, breast, prostate, colorectal, pancreatic, and lung cancers). The current findings in these cancers are summarized, and the relevant mechanisms and relationship between DUBs and cancers are discussed. In addition to highlighting the importance of DUBs in cancer biology, this study also provides updated information on the roles of DUBs in different types of cancers.
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Affiliation(s)
- Jiaqi LIU
- Key Laboratory of Environmental Pollution and Integrative Omics, Education Department of Guangxi Zhuang Autonomous Region, Guilin Medical University, Guilin 541004, China; (J.L.); (L.L.); (Y.W.); (K.P.L.)
| | - Chi Tim LEUNG
- Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China;
| | - Luyun LIANG
- Key Laboratory of Environmental Pollution and Integrative Omics, Education Department of Guangxi Zhuang Autonomous Region, Guilin Medical University, Guilin 541004, China; (J.L.); (L.L.); (Y.W.); (K.P.L.)
| | - Yuqin WANG
- Key Laboratory of Environmental Pollution and Integrative Omics, Education Department of Guangxi Zhuang Autonomous Region, Guilin Medical University, Guilin 541004, China; (J.L.); (L.L.); (Y.W.); (K.P.L.)
| | - Jian CHEN
- Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541004, China
- Correspondence: (J.C.); (W.K.F.T.); Tel.: +86-773-5895860 (J.C.); +81-92-802-4767 (W.K.F.T.)
| | - Keng Po LAI
- Key Laboratory of Environmental Pollution and Integrative Omics, Education Department of Guangxi Zhuang Autonomous Region, Guilin Medical University, Guilin 541004, China; (J.L.); (L.L.); (Y.W.); (K.P.L.)
| | - William Ka Fai TSE
- Laboratory of Developmental Disorders and Toxicology, Center for Promotion of International Education and Research, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan
- Correspondence: (J.C.); (W.K.F.T.); Tel.: +86-773-5895860 (J.C.); +81-92-802-4767 (W.K.F.T.)
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Shamis SA, Quinn J, Mallon EE, Edwards J, McMillan DC. The Relationship Between the Tumor Cell Expression of Hypoxic Markers and Survival in Patients With ER-positive Invasive Ductal Breast Cancer. J Histochem Cytochem 2022; 70:479-494. [PMID: 35792080 PMCID: PMC9284237 DOI: 10.1369/00221554221110280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The prognostic significance of hypoxia markers, hypoxia-inducible factor-1α
(HIF-1α), hypoxia-inducible factor-2α (HIF-2α), and carbonic anhydrase IX
(CAIX), was investigated in estrogen receptor (ER)-positive breast cancer
patients. Immunohistochemistry determined the expression of makers in two
independent ductal ER-positive cohorts (Training set, n=373 and
Validation set, n=285) and was related to clinicopathological
parameters and disease-free survival (DFS). In the training cohort, nuclear
HIF-1α (1) was independently associated with poorer DFS in luminal A tumors
[hazard ratio (HR) = 0.53 95% confidence interval (CI): 0.30–0.94,
p=0.030]. In the validation cohort, both HIF-1α (1) and
CAIX were independently associated with decreased DFS in the entire cohort (HR =
1.85 95% CI: 1.10–3.11, p=0.019; HR = 1.74 95% CI: 1.08–2.82,
p=0.023), in luminal A disease (HR = 1.98 95% CI:
1.02–3.83, p=0.042), and in luminal B disease (HR = 2.75 95%
CI: 1.66–4.55, p<0.001), respectively. Taken together,
elevated cytoplasmic HIF-1α (1) expression was an independent prognostic factor
in luminal A disease, whereas CAIX was an independent prognostic factor in
luminal B disease. Further work in large tissue cohorts is required.
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Affiliation(s)
- Suad A.K. Shamis
- Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow, United Kingdom
- Unit of Molecular Pathology, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Jean Quinn
- Unit of Molecular Pathology, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Elizabeth E.A. Mallon
- Department of Pathology, Queen Elizabeth University Hospital, Glasgow, United Kingdom
| | - Joanne Edwards
- Unit of Molecular Pathology, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Donald C. McMillan
- Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow, United Kingdom
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Zhang K, Wang J, Zhu Y, Liu X, Li J, Shi Z, Cao M, Li Y. Identification of Hub Genes Associated With the Development of Stomach Adenocarcinoma by Integrated Bioinformatics Analysis. Front Oncol 2022; 12:844990. [PMID: 35686089 PMCID: PMC9170954 DOI: 10.3389/fonc.2022.844990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 04/18/2022] [Indexed: 11/13/2022] Open
Abstract
Objective This study was conducted in order to gain a better understanding of the molecular mechanisms of stomach adenocarcinoma (STAD), which is necessary to predict the prognosis of STAD and develop novel gene therapy strategies. Methods In this study, the gene expression profile of GSE118916 in the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas Program (TCGA) was used to explore the differential co-expression genes of STAD and normal tissues. Results A total of 407 STAD samples were collected, consisting of 375 from stomach adenocarcinoma tissues and 32 from normal tissues, as well as RNA-seq count data for 19,600 genes. Forty-two differentially expressed genes were screened by weighted gene co-expression network analysis (WGCNA) and differentially expressed gene analysis. According to the functional annotation analysis of the clusterProfiler R package, these genes were analyzed for GO function enrichment, digestion (biological process), tube bottom material membrane (cell component), and oxidoreductase activity (molecular function). The KEGG pathway was enriched in gastric acid secretion and chemical carcinogenesis. In addition, Cytoscape's cytoHubba plug-in was used to identify seven hub genes (EWSR1, ESR1, CLTC, PCMT1, TP53, HUWE1, and HDAC1) in a protein-protein interaction (PPI) network consisting of 7 nodes and 11 edges. Compared with normal tissues, CLTC and TP53 genes were upregulated in stomach adenocarcinoma (P < 0.05). TP53 was expressed differently in stages II and IV, EWSR1 was expressed differently in stages II and III, and ESR1 was expressed differently in stages I-III. Among the seven hub genes, Kaplan-Meier analysis and TCGG showed that the expression levels of HDAC1 and CLTC were significantly correlated with OS in patients with stomach adenocarcinoma (P < 0.05). GEPIA2 analysis showed that ESR1 expression was closely correlated with OS and DFS in gastric adenocarcinoma (P < 0.05). Then, the expression of the genes and their correlations were revealed by the R2 Platform (http://r2.amc.nl). Finally, we collected 18 pairs of gastric mucosal tissues from normal people and cancer tissues from patients with stomach adenocarcinoma. The expression levels of the above seven hub genes and their relative protein expression were detected by RT-PCR and immunohistochemistry (IHC). The results showed that the gene and protein expression levels in stomach adenocarcinoma tissues were increased than those in the normal group. Conclusion In summary, we believe that the identified hub genes were related to the occurrence of stomach adenocarcinoma, especially the expression of ESR1, HDAC1, and CLTC genes, which are related to the prognosis and overall survival of patients and may become the potential for the future diagnosis and treatment of STAD.
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Affiliation(s)
- Kehui Zhang
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jian Wang
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - YingYing Zhu
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaolin Liu
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiacheng Li
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhe Shi
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mengxing Cao
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yong Li
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Pescatori S, Leone S, Cipolletti M, Bartoloni S, di Masi A, Acconcia F. Clinically relevant CHK1 inhibitors abrogate wild-type and Y537S mutant ERα expression and proliferation in luminal primary and metastatic breast cancer cells. J Exp Clin Cancer Res 2022; 41:141. [PMID: 35418303 PMCID: PMC9006609 DOI: 10.1186/s13046-022-02360-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 04/07/2022] [Indexed: 04/12/2023] Open
Abstract
BACKGROUND Challenges exist in the clinical treatment of luminal estrogen receptor α (ERα)-positive breast cancers (BCs) both to prevent resistance to endocrine therapy (ET) and to treat ET-resistant metastatic BCs (MBC). Therefore, we evaluated if kinases could be new targets for the treatment of luminal primary and MBCs. METHODS ~ 170 kinase inhibitors were applied to MCF-7 cells either with adaptative or genetic resistance to ET drugs and both ERα levels and cell proliferation were measured. Robust-Z-score calculation identified AZD7762 (CHK1/CHK2 inhibitor) as a positive hit. Subsequently, Kaplan-Meier analyses of CHK1 and CHK2 impact on ERα-positive BC patients relapse-free-survival (RFS), bioinformatic evaluations of CHK1 and CHK2 expression and activation status as a function of ERα activation status as well as drug sensitivity studies in ERα-positive BC cell lines, validation of the impact of the ATR:CHK1 and ATM:CHK2 pathways on the control of ERα stability and BC cell proliferation via inhibitor- and siRNA-based approaches, identification of the molecular mechanism required for inhibitor-dependent ERα degradation in BC and the impact of CHK1 and CHK2 inhibition on the 17β-estradiol (E2):ERα signaling, synergy proliferation studies between ET-drugs and clinically relevant CHK1 inhibitors in different luminal BC cell lines, were performed. RESULTS A reduced CHK1 expression correlates with a longer RFS in women with ERα-positive BCs. Interestingly, women carrying luminal A BC display an extended RFS when expressing low CHK1 levels. Accordingly, CHK1 and ERα activations are correlated in ERα-positive BC cell lines, and the ATR:CHK1 pathway controls ERα stability and cell proliferation in luminal A BC cells. Mechanistically, the generation of DNA replication stress rather than DNA damage induced by ATR:CHK1 pathway inhibition is a prerequisite for ERα degradation. Furthermore, CHK1 inhibition interferes with E2:ERα signaling to cell proliferation, and drugs approved for clinical treatment of primary and MBC (4OH-tamoxifen and the CDK4/CDK6 inhibitors abemaciclib and palbociclib) exert synergic effects with the CHK1 inhibitors in clinical trials for the treatment of solid tumors (AZD7762, MK8776, prexasertib) in preventing the proliferation of cells modeling primary and MBC. CONCLUSIONS CHK1 could be considered as an appealing novel pharmacological target for the treatment of luminal primary and MBCs.
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Affiliation(s)
- Sara Pescatori
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Stefano Leone
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Manuela Cipolletti
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Stefania Bartoloni
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Alessandra di Masi
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Filippo Acconcia
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy.
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Heo JH, Lee SR, Jo SL, Yang H, Lee HW, Hong EJ. Letrozole Accelerates Metabolic Remodeling through Activation of Glycolysis in Cardiomyocytes: A Role beyond Hormone Regulation. Int J Mol Sci 2022; 23:ijms23010547. [PMID: 35008972 PMCID: PMC8745349 DOI: 10.3390/ijms23010547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/23/2021] [Accepted: 01/01/2022] [Indexed: 02/04/2023] Open
Abstract
Estrogen receptor-positive (ER+) breast cancer patients are recommended hormone therapy as a primary adjuvant treatment after surgery. Aromatase inhibitors (AIs) are widely administered to ER+ breast cancer patients as estrogen blockers; however, their safety remains controversial. The use of letrozole, an AI, has been reported to cause adverse cardiovascular effects. We aimed to elucidate the effects of letrozole on the cardiovascular system. Female rats exposed to letrozole for four weeks showed metabolic changes, i.e., decreased fatty acid oxidation, increased glycolysis, and hypertrophy in the left ventricle. Although lipid oxidation yields more ATP than carbohydrate metabolism, the latter predominates in the heart under pathological conditions. Reduced lipid metabolism is attributed to reduced β-oxidation due to low circulating estrogen levels. In letrozole-treated rats, glycolysis levels were found to be increased in the heart. Furthermore, the levels of glycolytic enzymes were increased (in a high glucose medium) and the glycolytic rate was increased in vitro (H9c2 cells); the same was not true in the case of estrogen treatment. Reduced lipid metabolism and increased glycolysis can lower energy supply to the heart, resulting in predisposition to heart failure. These data suggest that a letrozole-induced cardiac metabolic remodeling, i.e., a shift from β-oxidation to glycolysis, may induce cardiac structural remodeling.
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Affiliation(s)
- Jun H. Heo
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea; (J.H.H.); (S.R.L.); (S.L.J.)
| | - Sang R. Lee
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea; (J.H.H.); (S.R.L.); (S.L.J.)
| | - Seong Lae Jo
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea; (J.H.H.); (S.R.L.); (S.L.J.)
| | - Hyun Yang
- KM Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea; (H.Y.); (H.W.L.)
| | - Hye Won Lee
- KM Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea; (H.Y.); (H.W.L.)
| | - Eui-Ju Hong
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea; (J.H.H.); (S.R.L.); (S.L.J.)
- Correspondence:
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Wang J, Yin J, Qiu J, Jiang J, Hu Y, Zhu K, Zheng H, Luo T, Zhong X. Comparison of dyslipidemia incidence in Chinese early-stage breast cancer patients following different endocrine therapies: A population-based cohort study. Front Endocrinol (Lausanne) 2022; 13:815960. [PMID: 36147563 PMCID: PMC9486544 DOI: 10.3389/fendo.2022.815960] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 08/16/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND There is lack of large-scale real-world research evidence showing the impact of endocrine therapy on blood lipids in Chinese breast cancer patients, especially those with premenopausal breast cancer. Based on a large breast cancer cohort at West China Hospital, we aimed to compare the risk of dyslipidemia between premenopausal and postmenopausal women based on the endocrine therapy used. METHODS A total of 1,883 early-stage breast cancer (EBC) patients who received endocrine monotherapy [selective estrogen receptor modulator (SERM) and aromatase inhibitor (AI), with or without ovarian function suppression] with normal blood lipid levels at baseline were retrospectively included between October 2008 and April 2017. Dyslipidemia was defined as an abnormality in cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein, and total cholesterol (TC) levels. The risk accumulation function was used to calculate the incidence of dyslipidemia in order to assess the absolute risk, while the multivariate Cox regression model was used to calculate the relative risk of dyslipidemia between the groups. RESULTS Patients with EBC were followed up for 60 months to monitor their blood lipid levels. The accumulated 5-year incidence of dyslipidemia in postmenopausal patients was higher than that in premenopausal patients (adjusted HR [95% confidence interval], 1.25 [1.01-1.56], 41.7% vs. 31.2%, p = 0.045). In premenopausal patients, the risk of abnormal TC was significantly higher in the OFS+AI group compared with that in the SERM group (adjusted HR [95% CI], 6.24 [3.19-12.20], p < 0.001, 5-year abnormal rates: 21.5% vs. 2.4%), and that of abnormal LDL-C level also increased (adjusted HR [95% CI], 10.54 [3.86-28.77], p < 0.001, 5-year abnormal rates: 11.1% vs. 0.9%). In postmenopausal patients, the risk of abnormal TC or LDL-C levels showed a similar trend in the AI and SERM groups. CONCLUSIONS In addition to postmenopausal patients, dyslipidemia is also common in premenopausal Chinese patients with EBC who received endocrine therapy. Irrespective of menopausal status, AI treatment increases the risk of TC/LDL-C dyslipidemia than SERM treatment.
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Affiliation(s)
- Junren Wang
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China
- Med-X Center for Informatics, Sichuan University, Chengdu, China
| | - Jin Yin
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China
- Med-X Center for Informatics, Sichuan University, Chengdu, China
- School of Computer Science and Engineering, University of Electronic Science and Technology of China, Chengdu, China
| | - Jiajun Qiu
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China
- Med-X Center for Informatics, Sichuan University, Chengdu, China
| | - Jingwen Jiang
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China
- Med-X Center for Informatics, Sichuan University, Chengdu, China
| | - Yao Hu
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China
- Med-X Center for Informatics, Sichuan University, Chengdu, China
| | - Kunrui Zhu
- Cancer Center, Breast Disease Center, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Molecular Diagnosis of Cancer, Clinical Research Center for Breast, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Zheng
- Cancer Center, Breast Disease Center, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Molecular Diagnosis of Cancer, Clinical Research Center for Breast, West China Hospital, Sichuan University, Chengdu, China
| | - Ting Luo
- Cancer Center, Breast Disease Center, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Molecular Diagnosis of Cancer, Clinical Research Center for Breast, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaorong Zhong
- Cancer Center, Breast Disease Center, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Molecular Diagnosis of Cancer, Clinical Research Center for Breast, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Xiaorong Zhong,
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Acconcia F, Fiocchetti M, Busonero C, Fernandez VS, Montalesi E, Cipolletti M, Pallottini V, Marino M. The extra-nuclear interactome of the estrogen receptors: implications for physiological functions. Mol Cell Endocrinol 2021; 538:111452. [PMID: 34500041 DOI: 10.1016/j.mce.2021.111452] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 08/19/2021] [Accepted: 09/02/2021] [Indexed: 02/07/2023]
Abstract
Over the last decades, a great body of evidence has defined a novel view of the cellular mechanism of action of the steroid hormone 17β-estradiol (E2) through its estrogen receptors (i.e., ERα and ERβ). It is now clear that the E2-activated ERs work both as transcription factors and extra-nuclear plasma membrane-localized receptors. The activation of a plethora of signal transduction cascades follows the E2-dependent engagement of plasma membrane-localized ERs and is required for the coordination of gene expression, which ultimately controls the occurrence of the pleiotropic effects of E2. The definition of the molecular mechanisms by which the ERs locate at the cell surface (i.e., palmitoylation and protein association) determined the quest for understanding the specificity of the extra-nuclear E2 signaling. The use of mice models lacking the plasma membrane ERα localization unveiled that the extra-nuclear E2 signaling is operational in vivo but tissue-specific. However, the underlying molecular details for such ERs signaling diversity in the perspective of the E2 physiological functions in the different cellular contexts are still not understood. Therefore, to gain insights into the tissue specificity of the extra-nuclear E2 signaling to physiological functions, here we reviewed the known ERs extra-nuclear interactors and tried to extrapolate from available databases the ERα and ERβ extra-nuclear interactomes. Based on literature data, it is possible to conclude that by specifically binding to extra-nuclear localized proteins in different sub-cellular compartments, the ERs fine-tune their molecular activities. Moreover, we report that the context-dependent diversity of the ERs-mediated extra-nuclear E2 actions can be ascribed to the great flexibility of the physical structures of ERs and the spatial-temporal organization of the logistics of the cells (i.e., the endocytic compartments). Finally, we provide lists of proteins belonging to the potential ERα and ERβ extra-nuclear interactomes and propose that the systematic experimental definition of the ERs extra-nuclear interactomes in different tissues represents the next step for the research in the ERs field. Such characterization will be fundamental for the identification of novel druggable targets for the innovative treatment of ERs-related diseases.
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Affiliation(s)
- Filippo Acconcia
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy.
| | - Marco Fiocchetti
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Claudia Busonero
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Virginia Solar Fernandez
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Emiliano Montalesi
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Manuela Cipolletti
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Valentina Pallottini
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Maria Marino
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy.
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Łukasiewicz S, Czeczelewski M, Forma A, Baj J, Sitarz R, Stanisławek A. Breast Cancer-Epidemiology, Risk Factors, Classification, Prognostic Markers, and Current Treatment Strategies-An Updated Review. Cancers (Basel) 2021; 13:4287. [PMID: 34503097 PMCID: PMC8428369 DOI: 10.3390/cancers13174287] [Citation(s) in RCA: 764] [Impact Index Per Article: 191.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/19/2021] [Accepted: 08/23/2021] [Indexed: 02/07/2023] Open
Abstract
Breast cancer (BC) is the most frequently diagnosed cancer in women worldwide with more than 2 million new cases in 2020. Its incidence and death rates have increased over the last three decades due to the change in risk factor profiles, better cancer registration, and cancer detection. The number of risk factors of BC is significant and includes both the modifiable factors and non-modifiable factors. Currently, about 80% of patients with BC are individuals aged >50. Survival depends on both stage and molecular subtype. Invasive BCs comprise wide spectrum tumors that show a variation concerning their clinical presentation, behavior, and morphology. Based on mRNA gene expression levels, BC can be divided into molecular subtypes (Luminal A, Luminal B, HER2-enriched, and basal-like). The molecular subtypes provide insights into new treatment strategies and patient stratifications that impact the management of BC patients. The eighth edition of TNM classification outlines a new staging system for BC that, in addition to anatomical features, acknowledges biological factors. Treatment of breast cancer is complex and involves a combination of different modalities including surgery, radiotherapy, chemotherapy, hormonal therapy, or biological therapies delivered in diverse sequences.
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Affiliation(s)
- Sergiusz Łukasiewicz
- Department of Surgical Oncology, Center of Oncology of the Lublin Region St. Jana z Dukli, 20-091 Lublin, Poland; (S.Ł.); (A.S.)
| | - Marcin Czeczelewski
- Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (M.C.); (A.F.)
| | - Alicja Forma
- Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (M.C.); (A.F.)
| | - Jacek Baj
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Robert Sitarz
- Department of Surgical Oncology, Center of Oncology of the Lublin Region St. Jana z Dukli, 20-091 Lublin, Poland; (S.Ł.); (A.S.)
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Andrzej Stanisławek
- Department of Surgical Oncology, Center of Oncology of the Lublin Region St. Jana z Dukli, 20-091 Lublin, Poland; (S.Ł.); (A.S.)
- Department of Oncology, Chair of Oncology and Environmental Health, Medical University of Lublin, 20-081 Lublin, Poland
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Biyik-Sit R, Kruer T, Dougherty S, Bradley JA, Wilkey DW, Merchant ML, Trent JO, Clem BF. Nuclear Pyruvate Kinase M2 (PKM2) Contributes to Phosphoserine Aminotransferase 1 (PSAT1)-Mediated Cell Migration in EGFR-Activated Lung Cancer Cells. Cancers (Basel) 2021; 13:cancers13163938. [PMID: 34439090 PMCID: PMC8391706 DOI: 10.3390/cancers13163938] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 01/04/2023] Open
Abstract
Simple Summary Alternative functions for metabolic proteins have recently been shown to drive cancer growth. These may include differential enzymatic activity or novel protein associations. Phosphoserine aminotransferase 1 (PSAT1) participates in cellular serine synthesis and has been observed to be elevated in different tumor types. In this study, we aimed to identify new putative PSAT1 activities and determine their contribution to lung tumor progression. We found a direct association for PSAT1 with another enzyme, pyruvate kinase M2. While this appears not to affect PKM2’s metabolic activity, PSAT1 is required for the specific cellular localization of PKM2 upon tumorigenic signaling. Further, the depletion of PSAT1 suppresses lung cancer cell movement that can be partially restored by the compartment expression of PKM2. These findings reveal a novel mechanism that is able to promote the spread of this deadly disease. Abstract An elevated expression of phosphoserine aminotransferase 1 (PSAT1) has been observed in multiple tumor types and is associated with poorer clinical outcomes. Although PSAT1 is postulated to promote tumor growth through its enzymatic function within the serine synthesis pathway (SSP), its role in cancer progression has not been fully characterized. Here, we explore a putative non-canonical function of PSAT1 that contributes to lung tumor progression. Biochemical studies found that PSAT1 selectively interacts with pyruvate kinase M2 (PKM2). Amino acid mutations within a PKM2-unique region significantly reduced this interaction. While PSAT1 loss had no effect on cellular pyruvate kinase activity and PKM2 expression in non-small-cell lung cancer (NSCLC) cells, fractionation studies demonstrated that the silencing of PSAT1 in epidermal growth factor receptor (EGFR)-mutant PC9 or EGF-stimulated A549 cells decreased PKM2 nuclear translocation. Further, PSAT1 suppression abrogated cell migration in these two cell types whereas PSAT1 restoration or overexpression induced cell migration along with an elevated nuclear PKM2 expression. Lastly, the nuclear re-expression of the acetyl-mimetic mutant of PKM2 (K433Q), but not the wild-type, partially restored cell migration in PSAT1-silenced cells. Therefore, we conclude that, in response to EGFR activation, PSAT1 contributes to lung cancer cell migration, in part, by promoting nuclear PKM2 translocation.
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Affiliation(s)
- Rumeysa Biyik-Sit
- Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40202, USA; (R.B.-S.); (T.K.); (S.D.); (J.A.B.)
| | - Traci Kruer
- Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40202, USA; (R.B.-S.); (T.K.); (S.D.); (J.A.B.)
| | - Susan Dougherty
- Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40202, USA; (R.B.-S.); (T.K.); (S.D.); (J.A.B.)
| | - James A. Bradley
- Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40202, USA; (R.B.-S.); (T.K.); (S.D.); (J.A.B.)
| | - Daniel W. Wilkey
- Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, KY 40202, USA; (D.W.W.); (M.L.M.)
| | - Michael L. Merchant
- Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, KY 40202, USA; (D.W.W.); (M.L.M.)
| | - John O. Trent
- Department of Medicine, Division of Hematology and Oncology, University of Louisville School of Medicine, Louisville, KY 40202, USA;
- Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Brian F. Clem
- Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40202, USA; (R.B.-S.); (T.K.); (S.D.); (J.A.B.)
- Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40202, USA
- Correspondence: ; Tel.: +1-502-852-8427
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NR4A1 Regulates Tamoxifen Resistance by Suppressing ERK Signaling in ER-Positive Breast Cancer. Cells 2021; 10:cells10071633. [PMID: 34209871 PMCID: PMC8307977 DOI: 10.3390/cells10071633] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/18/2021] [Accepted: 06/28/2021] [Indexed: 11/18/2022] Open
Abstract
Endocrine therapy is used to treat estrogen receptor (ER)-positive breast cancer. Tamoxifen is effective against this cancer subtype. Nonetheless, approximately 30% of patients treated with tamoxifen acquire resistance, resulting in therapeutic challenges. NR4A1 plays key roles in processes associated with carcinogenesis, apoptosis, DNA repair, proliferation, and inflammation. However, the role of NR4A1 in tamoxifen-resistant ER-positive breast cancer has not yet been elucidated. Here, we propose that NR4A1 is a promising target to overcome tamoxifen resistance. NR4A1 gene expression was downregulated in tamoxifen-resistant MCF7 (TamR) cells compared to that in MCF7 cells. Kaplan-Meier plots were used to identify high NR4A1 expression correlated with increased survival rates in patients with ER-positive breast cancer following tamoxifen treatment. Gain and loss of function experiments showed that NR4A1 restores sensitivity to tamoxifen by regulating cell proliferation, migration, invasion, and apoptosis. NR4A1 localized to the cytoplasm enhanced the expression of apoptotic factors. In silico and in vitro analyses revealed that NR4A1 enhanced responsiveness to tamoxifen by suppressing ERK signaling in ER-positive breast cancer, suggesting that the NR4A1/ERK signaling axis modulates tamoxifen resistance. These results indicate that NR4A1 could be a potential therapeutic target to overcome tamoxifen resistance in ER-positive breast cancer.
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NR4A1 Regulates Tamoxifen Resistance by Suppressing ERK Signaling in ER-Positive Breast Cancer. Cells 2021. [PMID: 34209871 DOI: 10.3390/cells10071633/s1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2023] Open
Abstract
Endocrine therapy is used to treat estrogen receptor (ER)-positive breast cancer. Tamoxifen is effective against this cancer subtype. Nonetheless, approximately 30% of patients treated with tamoxifen acquire resistance, resulting in therapeutic challenges. NR4A1 plays key roles in processes associated with carcinogenesis, apoptosis, DNA repair, proliferation, and inflammation. However, the role of NR4A1 in tamoxifen-resistant ER-positive breast cancer has not yet been elucidated. Here, we propose that NR4A1 is a promising target to overcome tamoxifen resistance. NR4A1 gene expression was downregulated in tamoxifen-resistant MCF7 (TamR) cells compared to that in MCF7 cells. Kaplan-Meier plots were used to identify high NR4A1 expression correlated with increased survival rates in patients with ER-positive breast cancer following tamoxifen treatment. Gain and loss of function experiments showed that NR4A1 restores sensitivity to tamoxifen by regulating cell proliferation, migration, invasion, and apoptosis. NR4A1 localized to the cytoplasm enhanced the expression of apoptotic factors. In silico and in vitro analyses revealed that NR4A1 enhanced responsiveness to tamoxifen by suppressing ERK signaling in ER-positive breast cancer, suggesting that the NR4A1/ERK signaling axis modulates tamoxifen resistance. These results indicate that NR4A1 could be a potential therapeutic target to overcome tamoxifen resistance in ER-positive breast cancer.
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Kasiotis KM, Lambrinidis G, Fokialakis N, Haroutounian SA. Novel Carbamοyloxy Analogues of Tamoxifen: Synthesis, Molecular Docking and Bioactivity Evaluation. LETT DRUG DES DISCOV 2021. [DOI: 10.2174/1570180817999201104125630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:
Tamoxifen (TAM), a non-steroidal antiestrogen, constitutes the endocrine
treatment of choice against breast cancer. Since its inauguration, substantial effort has been devoted
towards the design and synthesis of TAM’s analogues aiming to improve its bioactivity and reveal
their structure-activity relationship.
Objective:
One of the most studied synthetic features of TAM’s structure is the ether side chain,
which is strongly related to its positioning into the active site of the Estrogen Receptors (ERα and
ERβ). Herein, we present the application of a straightforward route for the efficient synthesis of
selected novel carbamoyloxy analogues of TAM and the evaluation of their respective binding affinities
to the Estrogen Receptors α and β.
Methods:
A one-pot reaction was applied for the construction of TAM’s triarylethylene core moiety,
which subsequently was derivatized to provide efficiently the target carbamoyloxy analogues of
TAM. The Z and E isomers of the latter were separated using RP-HPLC-UV and their binding affinities
to ERα and ERβ were measured.
Results:
Among all compounds synthesized, the dimethyl derivative was determined as the most
potent for both receptors, displaying binding affinity values comparable to TAM, though the Zdiethyl
analogue maintained substantial affinity to both ERs. The aforementioned results were further
studied by theoretical calculations and molecular modelling to delineate a concordance among
calculations and biological activity.
Conclusion:
Approach applied herein permitted the extraction of a useful structure-activity relationship
correlation pattern highlighting the importance of a chemically stabilized tamoxifen side chain.
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Affiliation(s)
- Konstantinos M. Kasiotis
- Laboratory of Pesticides’ Toxicology, Department of Pesticides Control and Phytopharmacy, Benaki Phytopathological Institute, 8 Stefanou Delta Street, Athens, Kifissia 14561,Greece
| | - George Lambrinidis
- Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, 15771, Athens,Greece
| | - Nikolas Fokialakis
- Division of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, 15771, Athens,Greece
| | - Serkos A. Haroutounian
- Laboratory of Nutritional Physiology and Feeding, Faculty of Animal Sciences and Aquaculture, Agricultural University of Athens, Iera odos 75, Athens 11855,Greece
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Pescatori S, Berardinelli F, Albanesi J, Ascenzi P, Marino M, Antoccia A, di Masi A, Acconcia F. A Tale of Ice and Fire: The Dual Role for 17β-Estradiol in Balancing DNA Damage and Genome Integrity. Cancers (Basel) 2021; 13:1583. [PMID: 33808099 PMCID: PMC8036963 DOI: 10.3390/cancers13071583] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 03/24/2021] [Accepted: 03/26/2021] [Indexed: 12/21/2022] Open
Abstract
17β-estradiol (E2) regulates human physiology both in females and in males. At the same time, E2 acts as a genotoxic substance as it could induce DNA damages, causing the initiation of cellular transformation. Indeed, increased E2 plasma levels are a risk factor for the development of several types of cancers including breast cancer. This paradoxical identity of E2 undermines the foundations of the physiological definition of "hormone" as E2 works both as a homeostatic regulator of body functions and as a genotoxic compound. Here, (i) the molecular circuitries underlying this double face of E2 are reviewed, and (ii) a possible framework to reconcile the intrinsic discrepancies of the E2 function is reported. Indeed, E2 is a regulator of the DNA damage response, which this hormone exploits to calibrate its genotoxicity with its physiological effects. Accordingly, the genes required to maintain genome integrity belong to the E2-controlled cellular signaling network and are essential for the appearance of the E2-induced cellular effects. This concept requires an "upgrade" to the vision of E2 as a "genotoxic hormone", which balances physiological and detrimental pathways to guarantee human body homeostasis. Deregulation of this equilibrium between cellular pathways would determine the E2 pathological effects.
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Affiliation(s)
- Sara Pescatori
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146 Rome, Italy; (S.P.); (F.B.); (J.A.); (P.A.); (M.M.)
| | - Francesco Berardinelli
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146 Rome, Italy; (S.P.); (F.B.); (J.A.); (P.A.); (M.M.)
- Neurodevelopment, Neurogenetics and Molecular Neurobiology Unit, IRCCS Santa Lucia Foundation, 00143 Rome, Italy
| | - Jacopo Albanesi
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146 Rome, Italy; (S.P.); (F.B.); (J.A.); (P.A.); (M.M.)
| | - Paolo Ascenzi
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146 Rome, Italy; (S.P.); (F.B.); (J.A.); (P.A.); (M.M.)
- Neuroendocrinology, Metabolism and Neuropharmacology Unit, IRCCS Santa Lucia Foundation, 00143 Rome, Italy
| | - Maria Marino
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146 Rome, Italy; (S.P.); (F.B.); (J.A.); (P.A.); (M.M.)
- Neuroendocrinology, Metabolism and Neuropharmacology Unit, IRCCS Santa Lucia Foundation, 00143 Rome, Italy
| | - Antonio Antoccia
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146 Rome, Italy; (S.P.); (F.B.); (J.A.); (P.A.); (M.M.)
| | - Alessandra di Masi
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146 Rome, Italy; (S.P.); (F.B.); (J.A.); (P.A.); (M.M.)
| | - Filippo Acconcia
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146 Rome, Italy; (S.P.); (F.B.); (J.A.); (P.A.); (M.M.)
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A New Anti-Estrogen Discovery Platform Identifies FDA-Approved Imidazole Anti-Fungal Drugs as Bioactive Compounds against ERα Expressing Breast Cancer Cells. Int J Mol Sci 2021; 22:ijms22062915. [PMID: 33805656 PMCID: PMC8000495 DOI: 10.3390/ijms22062915] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/09/2021] [Accepted: 03/11/2021] [Indexed: 12/22/2022] Open
Abstract
17β-estradiol (E2) exerts its physiological effects through the estrogen receptor α (i.e., ERα). The E2:ERα signaling allows the regulation of cell proliferation. Indeed, E2 sustains the progression of ERα positive (ERα+) breast cancers (BCs). The presence of ERα at the BC diagnosis drives their therapeutic treatment with the endocrine therapy (ET), which restrains BC progression. Nonetheless, many patients develop metastatic BCs (MBC) for which a treatment is not available. Consequently, the actual challenge is to complement the drugs available to fight ERα+ primary and MBC. Here we exploited a novel anti-estrogen discovery platform to identify new Food and Drug Administration (FDA)-approved drugs inhibiting E2:ERα signaling to cell proliferation in cellular models of primary and MBC cells. We report that the anti-fungal drugs clotrimazole (Clo) and fenticonazole (Fenti) induce ERα degradation and prevent ERα transcriptional signaling and proliferation in cells modeling primary and metastatic BC. The anti-proliferative effects of Clo and Fenti occur also in 3D cancer models (i.e., tumor spheroids) and in a synergic manner with the CDK4/CDK6 inhibitors palbociclib and abemaciclib. Therefore, Clo and Fenti behave as “anti-estrogens”-like drugs. Remarkably, the present “anti-estrogen” discovery platform represents a valuable method to rapidly identify bioactive compounds with anti-estrogenic activity.
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Abstract
Metastatic estrogen receptor α (ERα)-expressing breast cancer (BC) occurs after prolonged patient treatment with endocrine therapy (ET) (e.g., aromatase inhibitors—AI; 4OH-tamoxifen—4OH-Tam). Often these metastatic BCs express a mutated ERα variant (e.g., Y537S), which is transcriptionally hyperactive, sustains uncontrolled proliferation, and renders tumor cells insensitive to ET drugs. Therefore, new molecules blocking hyperactive Y537S ERα mutation transcriptional activity are requested. Here we generated an MCF-7 cell line expressing the Y537S ERα mutation stably expressing an estrogen-responsive element (ERE) promoter, which activity can be monitored in living cells. Characterization of this cell line shows both hyperactive basal transcriptional activity with respect to normal MCF-7 cells, which stably express the same ERE-based promoter and a decreased effect of selective ER downregulators (SERDs) in reducing Y537S ERα mutant transcriptional activity with respect to wild type ERα transcriptional activity. Kinetic profiles of Y537S ERα mutant-based transcription produced by both drugs inducing receptor degradation and siRNA-mediated depletion of specific proteins (e.g., FOXA1 and caveolin1) reveals biphasic dynamics of the inhibition of the receptor-regulated transcriptional effects. Overall, we report a new model where to study the behavior of the Y537S ERα mutant that can be used for the identification of new targets and pathways regulating the Y537S ERα transcriptional activity.
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López-Sánchez LM, Mena R, Guil-Luna S, Mantrana A, Peñarando J, Toledano-Fonseca M, Conde F, De la Haba-Rodríguez JR, Aranda E, Rodríguez-Ariza A. Nitric oxide-targeted therapy inhibits stemness and increases the efficacy of tamoxifen in estrogen receptor-positive breast cancer cells. J Transl Med 2021; 101:292-303. [PMID: 33262438 DOI: 10.1038/s41374-020-00507-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 10/28/2020] [Accepted: 10/29/2020] [Indexed: 01/20/2023] Open
Abstract
Cancer stem cells (CSCs) are involved in the resistance of estrogen (ER)-positive breast tumors against endocrine therapy. On the other hand, nitric oxide (NO) plays a relevant role in CSC biology, although there are no studies addressing how this important signaling molecule may contribute to resistance to antihormonal therapy in ER+ breast cancer. Therefore, we explored whether targeting NO in ER+ breast cancer cells impacts CSC subpopulation and sensitivity to hormonal therapy with tamoxifen. NO was targeted in ER+ breast cancer cells by specific NO depletion and NOS2 silencing and mammosphere formation capacity, stem cell markers and tamoxifen sensitivity were analyzed. An orthotopic breast tumor model in mice was also performed to analyze the efficacy of NO-targeted therapy plus tamoxifen. Kaplan-Meier curves were made to analyze the association of NOS2 gene expression with survival of ER+ breast cancer patients treated with tamoxifen. Our results show that targeting NO inhibited mamosphere formation, CSC markers expression and increased the antitumoral efficacy of tamoxifen in ER+ breast cancer cells, whereas tamoxifen-resistant cells displayed higher expression levels of NOS2 and Notch-1 compared with parental cells. Notably, NO-targeted therapy plus tamoxifen was more effective than either treatment alone in an orthotopic breast tumor model in immunodeficient mice. Furthermore, low NOS2 expression was significantly associated with a higher metastasis-free survival in ER+ breast cancer patients treated with tamoxifen. In conclusion, our data support that NO-targeted therapy in ER+ breast cancer may contribute to increase the efficacy of antihormonal therapy avoiding the development of resistance to these treatments.
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Affiliation(s)
- Laura M López-Sánchez
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Rafael Mena
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
| | - Silvia Guil-Luna
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Ana Mantrana
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
| | - Jon Peñarando
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
| | - Marta Toledano-Fonseca
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Francisco Conde
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
| | - Juan R De la Haba-Rodríguez
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Unidad de Gestión Clínica de Oncología Médica, Hospital Universitario Reina Sofía, Córdoba, Spain
| | - Enrique Aranda
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Unidad de Gestión Clínica de Oncología Médica, Hospital Universitario Reina Sofía, Córdoba, Spain
- Departamento de Medicina, Facultad de Medicina, Universidad de Córdoba, Córdoba, Spain
| | - Antonio Rodríguez-Ariza
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain.
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
- Unidad de Gestión Clínica de Oncología Médica, Hospital Universitario Reina Sofía, Córdoba, Spain.
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Rugo HS, Huober J, García‐Sáenz JA, Masuda N, Sohn JH, Andre VA, Barriga S, Cox J, Goetz M. Management of Abemaciclib-Associated Adverse Events in Patients with Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Safety Analysis of MONARCH 2 and MONARCH 3. Oncologist 2021; 26:e53-e65. [PMID: 32955138 PMCID: PMC7794176 DOI: 10.1002/onco.13531 10.1002/onco.13531] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 08/14/2020] [Indexed: 02/07/2024] Open
Abstract
BACKGROUND Abemaciclib demonstrated efficacy in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Here we provide a comprehensive summary of the most common adverse events (AEs), their management, and whether AEs or dose reductions influenced progression-free survival (PFS), in the MONARCH 2 and 3 trials. MATERIALS AND METHODS Incidence of the most clinically relevant AEs, management, and outcomes were summarized. Time-dependent covariate analyses examined the impact of dose reductions on PFS. PFS was estimated for patients with and without early onset of diarrhea or neutropenia. RESULTS The most frequently reported AE was diarrhea, with clinically significant diarrhea (grade ≥2) reported for 42.8% of patients taking abemaciclib. Median time to onset was 1 week, and duration ranged from 6 to 12 days, depending on grade and study. Diarrhea was adequately managed by antidiarrheal medication (72.8%), dose omissions (17.3%), and reductions (16.7%). The highest rates of grade ≥2 diarrhea were observed in the first cycles and decreased in subsequent cycles. Neutropenia (grade ≥3) occurred in 25.4% of abemaciclib-treated patients. Neutropenia resolved with dose omissions (16.8%) and/or dose reductions (11.2%). Incidence of febrile neutropenia (0.7%) or other relevant grade ≥3 hematological events (<9%) was low. Venous thromboembolic events (5.3%) were primarily treated with anticoagulants. Interstitial lung disease/pneumonitis (3.4%) was treated with corticosteroids and/or antibiotics. PFS benefit of abemaciclib was not impacted by dose reductions or early onset of toxicities. CONCLUSION Abemaciclib was generally well tolerated. The most common AEs were effectively managed by supportive medications, and/or dose adjustments, with no detriment to PFS. IMPLICATIONS FOR PRACTICE Treatment with abemaciclib plus fulvestrant or nonsteroidal aromatase inhibitors is generally well tolerated in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. In MONARCH 2 and MONARCH 3, any-grade diarrhea and grade ≥3 neutropenia were effectively managed with supportive medication and/or dose adjustment. Venous thromboembolic events were treated with anticoagulants and did not often require treatment discontinuation. Interstitial lung disease/pneumonitis was infrequent and treated with corticosteroids and/or antibiotics. Clinicians should be aware of and implement management strategies, including dose adjustments according to local labels, for commonly occurring and serious adverse events to ensure continued treatment and optimize clinical benefit/risk ratio.
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Affiliation(s)
- Hope S. Rugo
- University of California San Francisco Helen Diller Family Comprehensive Cancer CenterSan FranciscoCaliforniaUSA
| | | | - José A. García‐Sáenz
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Hospital Clínico San CarlosMadridSpain
| | - Norikazu Masuda
- National Hospital Organization Osaka National HospitalOsakaJapan
| | | | | | | | - Joanne Cox
- Eli Lilly and CompanySurreyUnited Kingdom
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Rugo HS, Huober J, García‐Sáenz JA, Masuda N, Sohn JH, Andre VA, Barriga S, Cox J, Goetz M. Management of Abemaciclib-Associated Adverse Events in Patients with Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Safety Analysis of MONARCH 2 and MONARCH 3. Oncologist 2021; 26:e53-e65. [PMID: 32955138 PMCID: PMC7794176 DOI: 10.1002/onco.13531] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 08/14/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Abemaciclib demonstrated efficacy in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Here we provide a comprehensive summary of the most common adverse events (AEs), their management, and whether AEs or dose reductions influenced progression-free survival (PFS), in the MONARCH 2 and 3 trials. MATERIALS AND METHODS Incidence of the most clinically relevant AEs, management, and outcomes were summarized. Time-dependent covariate analyses examined the impact of dose reductions on PFS. PFS was estimated for patients with and without early onset of diarrhea or neutropenia. RESULTS The most frequently reported AE was diarrhea, with clinically significant diarrhea (grade ≥2) reported for 42.8% of patients taking abemaciclib. Median time to onset was 1 week, and duration ranged from 6 to 12 days, depending on grade and study. Diarrhea was adequately managed by antidiarrheal medication (72.8%), dose omissions (17.3%), and reductions (16.7%). The highest rates of grade ≥2 diarrhea were observed in the first cycles and decreased in subsequent cycles. Neutropenia (grade ≥3) occurred in 25.4% of abemaciclib-treated patients. Neutropenia resolved with dose omissions (16.8%) and/or dose reductions (11.2%). Incidence of febrile neutropenia (0.7%) or other relevant grade ≥3 hematological events (<9%) was low. Venous thromboembolic events (5.3%) were primarily treated with anticoagulants. Interstitial lung disease/pneumonitis (3.4%) was treated with corticosteroids and/or antibiotics. PFS benefit of abemaciclib was not impacted by dose reductions or early onset of toxicities. CONCLUSION Abemaciclib was generally well tolerated. The most common AEs were effectively managed by supportive medications, and/or dose adjustments, with no detriment to PFS. IMPLICATIONS FOR PRACTICE Treatment with abemaciclib plus fulvestrant or nonsteroidal aromatase inhibitors is generally well tolerated in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. In MONARCH 2 and MONARCH 3, any-grade diarrhea and grade ≥3 neutropenia were effectively managed with supportive medication and/or dose adjustment. Venous thromboembolic events were treated with anticoagulants and did not often require treatment discontinuation. Interstitial lung disease/pneumonitis was infrequent and treated with corticosteroids and/or antibiotics. Clinicians should be aware of and implement management strategies, including dose adjustments according to local labels, for commonly occurring and serious adverse events to ensure continued treatment and optimize clinical benefit/risk ratio.
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Affiliation(s)
- Hope S. Rugo
- University of California San Francisco Helen Diller Family Comprehensive Cancer CenterSan FranciscoCaliforniaUSA
| | | | - José A. García‐Sáenz
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Hospital Clínico San CarlosMadridSpain
| | - Norikazu Masuda
- National Hospital Organization Osaka National HospitalOsakaJapan
| | | | | | | | - Joanne Cox
- Eli Lilly and CompanySurreyUnited Kingdom
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Liu Y, Zhang N, Zhang H, Wang L, Duan Y, Wang X, Chen T, Liang Y, Li Y, Song X, Li C, Han D, Chen B, Zhao W, Yang Q. Fatostatin in Combination with Tamoxifen Induces Synergistic Inhibition in ER-Positive Breast Cancer. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:3535-3545. [PMID: 32921987 PMCID: PMC7457819 DOI: 10.2147/dddt.s253876] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 07/31/2020] [Indexed: 12/18/2022]
Abstract
Background Tamoxifen is the cornerstone of adjuvant therapy for hormone receptor-positive breast cancer. Despite its efficacy, limited drug sensitivity and endocrine resistance remain the important clinical challenges. The main objective of this study was to investigate fatostatin, which was found to sensitize breast cancer to the antitumour effect of tamoxifen both in vitro and in vivo. Methods Fatostatin-induced ER degradation was detected by immunoprecipitation assay. The antitumour effect of fatostatin and tamoxifen on MCF-7 and T47D cells was assessed by MTT and colony forming assays. Cell cycle arrest was detected by flow cytometric analysis. Apoptosis was detected by annexin V/propidium iodide double staining and TUNEL assay. Autophagy was detected by MDC assay and acridine orange staining. Migration and invasion assays were performed using a Transwell system, and the efficacy of the synergistic use of fatostatin and tamoxifen in vivo was evaluated using an MCF-7 xenograft model in BALB/c nu/nu female mice. Results The synergistic use of fatostatin and tamoxifen significantly suppressed cell viability and invasion, induced cell cycle arrest, and regulated apoptosis and autophagy in MCF-7 and T47D cell lines via PI3K-AKT-mTOR signalling. Additionally, the expression levels of Atg7/12/13, beclin and LC3B increased while p-mTOR and P62 expression levels decreased after treatment with fatostatin and tamoxifen. Tumor growth in the xenograft model was suppressed significantly with the synergistic treatment of fatostatin and tamoxifen. Conclusion Fatostatin could induce ER degradation by K48-linked polyubiquitination, which was the key mechanism contributing to tamoxifen inhibition of PI3K-AKT-mTOR signalling in breast cancer. Fatostatin may have a promising clinical use for ER-positive breast cancer patients.
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Affiliation(s)
- Ying Liu
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China
| | - Ning Zhang
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China
| | - Hanwen Zhang
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China
| | - Lijuan Wang
- Pathology Tissue Bank, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China
| | - Yi Duan
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China
| | - Xiaolong Wang
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China
| | - Tong Chen
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China
| | - Yiran Liang
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China
| | - Yaming Li
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China
| | - Xiaojin Song
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China
| | - Chen Li
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China
| | - Dianwen Han
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China
| | - Bing Chen
- Pathology Tissue Bank, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China
| | - Wenjing Zhao
- Pathology Tissue Bank, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China
| | - Qifeng Yang
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China.,Pathology Tissue Bank, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China
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Batool A, Arshad R, Razzaq S, Nousheen K, Kiani MH, Shahnaz G. Formulation and evaluation of hyaluronic acid-based mucoadhesive self nanoemulsifying drug delivery system (SNEDDS) of tamoxifen for targeting breast cancer. Int J Biol Macromol 2020; 152:503-515. [DOI: 10.1016/j.ijbiomac.2020.02.275] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 02/23/2020] [Accepted: 02/24/2020] [Indexed: 01/09/2023]
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