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Ma M, An J, Jiang T, Xie K. GATA6 in pancreatic cancer initiation and progression. Genes Dis 2025; 12:101353. [PMID: 39717718 PMCID: PMC11665347 DOI: 10.1016/j.gendis.2024.101353] [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: 11/13/2023] [Revised: 03/28/2024] [Accepted: 05/29/2024] [Indexed: 12/25/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy characterized by insidious onset and lack of effective therapy. The molecular pathogenesis of PDA remains to be understood fully. Transcriptional factor GATA6 is an important transcriptional regulator in normal pancreas development, particularly in the initial specification and differentiation of the pancreas. Recent studies have linked pancreatic malignancy closely to GATA6. Increased levels of GATA6 expression enhance pancreatic cancer cell growth. GATA6 emerges as a lineage-specific oncogenic factor in PDA, augmenting the oncogenic phenotypes of PDA cells upon its overexpression. However, elevated GATA6 levels are correlated with well-differentiated tumors and a more favorable patient prognosis. Experimental evidence in genetic mouse models has revealed a tumor-suppressive role for GATA6. The circumstantial roles of GATA6 in pancreatic tumorigenesis remain to be defined. This review aims to elucidate recent advances in comprehending GATA6, emphasizing its crucial roles in both pancreas physiology and pathology. Special attention will be given to its involvement in PDA pathogenesis, exploring its potential as a novel biomarker and a promising therapeutic target for PDA.
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Affiliation(s)
- Muyuan Ma
- Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, Guangdong 510006, China
| | - Jianhong An
- Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, Guangdong 510006, China
| | - Tingting Jiang
- Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, Guangdong 510006, China
| | - Keping Xie
- Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, Guangdong 510006, China
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2
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Monsia R, Bhattacharyya S. Efficient and Explainable Virtual Screening of Molecules through Fingerprint-Generating Networks Integrated with Artificial Neural Networks. ACS OMEGA 2025; 10:4896-4911. [PMID: 39959102 PMCID: PMC11822703 DOI: 10.1021/acsomega.4c10289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 01/07/2025] [Accepted: 01/13/2025] [Indexed: 02/18/2025]
Abstract
A machine learning-based drug screening technique has been developed and optimized using a novel, stitched neural network architecture with trainable, graph convolution-based fingerprints as a base into an artificial neural network. The architecture is efficient, explainable, and performant as a tool for the binary classification of ligands based on a user-chosen docking score threshold. Assessment using two standardized virtual screening databases substantiated the architecture's ability to learn molecular features and substructures and predict ligand classes based on binding affinity values more effectively than similar contemporary counterparts. Furthermore, to highlight the architecture's utility to groups and laboratories with varying resources, experiments were carried out using randomly sampled small molecules from the ZINC database and their computational docking scores against six drug-design relevant proteins. This new architecture proved to be more efficient in screening molecules that less favorably bind to a specific target thereby retaining top-hit molecules. Compared to similar protocols developed using Morgan fingerprints, the neural fingerprint-based model shows superiority in retaining the best ligands while filtering molecules at a higher relative rate. Lastly, the explainability of the model was investigated; it was revealed that the model accurately emphasized important chemical substructures and atoms through the intermediate fingerprint, which, in turn, contributed heavily to the ultimate prediction of a ligand as binding tightly to a certain protein.
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Affiliation(s)
| | - Sudeep Bhattacharyya
- Department of Chemistry and
Biochemistry, University of Wisconsin—Eau
Claire, Eau Claire, Wisconsin 54701, United States
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3
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MacDonald WJ, Purcell C, Pinho-Schwermann M, Stubbs NM, Srinivasan PR, El-Deiry WS. Heterogeneity in Cancer. Cancers (Basel) 2025; 17:441. [PMID: 39941808 PMCID: PMC11816170 DOI: 10.3390/cancers17030441] [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: 12/19/2024] [Revised: 01/21/2025] [Accepted: 01/23/2025] [Indexed: 02/16/2025] Open
Abstract
Cancer heterogeneity is a major challenge in oncology, complicating diagnosis, prognostication, and treatment. The clinical heterogeneity of cancer, which leads to differential treatment outcomes between patients with histopathologically similar cancers, is attributable to molecular diversity manifesting through genetic, epigenetic, transcriptomic, microenvironmental, and host biology differences. Heterogeneity is observed between patients, individual metastases, and within individual lesions. This review discusses clinical implications of heterogeneity, emphasizing need for personalized approaches to overcome challenges posed by cancer's diverse presentations. Understanding of emerging molecular diagnostic and analytical techniques can provide a view into the multidimensional complexity of cancer heterogeneity. With over 90% of cancer-related deaths associated with metastasis, we additionally explore the role heterogeneity plays in treatment resistance and recurrence of metastatic lesions. Molecular insights from next-generation sequencing, single-cell transcriptomics, liquid biopsy technology, and artificial intelligence will facilitate the development of combination therapy regimens that can potentially induce lasting and even curative treatment outcomes.
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Affiliation(s)
- William J. MacDonald
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA; (W.J.M.); (M.P.-S.); (N.M.S.)
- Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
- Legorreta Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
| | - Connor Purcell
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA; (W.J.M.); (M.P.-S.); (N.M.S.)
- Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
- Legorreta Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
| | - Maximilian Pinho-Schwermann
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA; (W.J.M.); (M.P.-S.); (N.M.S.)
- Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
- Legorreta Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
| | - Nolan M. Stubbs
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA; (W.J.M.); (M.P.-S.); (N.M.S.)
- Legorreta Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
- Morehouse School of Medicine, Atlanta, GA 30310, USA
| | - Praveen R. Srinivasan
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA; (W.J.M.); (M.P.-S.); (N.M.S.)
- Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
- Legorreta Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
| | - Wafik S. El-Deiry
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA; (W.J.M.); (M.P.-S.); (N.M.S.)
- Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
- Legorreta Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
- The Joint Program in Cancer Biology, Brown University and Brown University Health, Providence, RI 02903, USA
- Hematology-Oncology Division, Department of Medicine, Rhode Island Hospital, Brown University, Providence, RI 02903, USA
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4
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Das S, Pattnaik G, Pattanaik S, Jena BR, Satapathy BS, Pradhan A. Envisioning Clinical Management of Breast Cancer: a Comprehensive Review. Curr Drug Discov Technol 2025; 22:e290424229495. [PMID: 38685777 DOI: 10.2174/0115701638300812240417055802] [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: 01/02/2024] [Revised: 02/29/2024] [Accepted: 03/12/2024] [Indexed: 05/02/2024]
Abstract
BACKGROUND Background: Coming to the edge of disease manufacturing in the twenty-- first-century, breast cancer occupies a terrifying scenario in the globe, especially in adult women. Its curiosity endeavours remarkable advances made during the past decennaries for cancer treatment and diagnosis. OBJECTIVE It accounts for the fifth leading cause of transience, killing approximately 570,000 people per annum. To reduce the prognosis of clinical oncological development with the application of a new chemical entity, some of the critical challenges, like active pharmaceutical ingredients with high chemical resistance, extreme side effects, and high treatment costs are some of the limitations in the curbing aspects of breast melanoma. METHODS In cancer research, hence, the development of drugs that are safe, efficient, and cost-effective remains a 'Holy Grail' that may be considered as a boon to target the malignant tissues with novel therapeutics devices. RESULTS Through the findings on overcoming the drawbacks of traditional methods, researchers have given special attention to cancer-preventive and theranostic approaches based on some novel drug delivery systems. CONCLUSION The present study forecasts the wide-ranging modern applications, and on developing some novel liposomal drug delivery therapy against breast cancer.
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Affiliation(s)
- Shubhashree Das
- School of Pharmacy and Life Sciences, Centurion University of Technology and Management, Jatani, 752050, Odisha, India
| | - Gurudutta Pattnaik
- School of Pharmacy and Life Sciences, Centurion University of Technology and Management, Jatani, 752050, Odisha, India
| | - Sovan Pattanaik
- School of Pharmaceutical Sciences, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, Jatani, 752050, Odisha, India
| | - Bikash Ranjan Jena
- School of Pharmacy and Life Sciences, Centurion University of Technology and Management, Jatani, 752050, Odisha, India
| | - Bhabani Sankar Satapathy
- School of Pharmaceutical Sciences, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, Jatani, 752050, Odisha, India
| | - Ayushi Pradhan
- School of Pharmacy and Life Sciences, Centurion University of Technology and Management, Jatani, 752050, Odisha, India
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5
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Li Z, Chen F, Chen L, Liu J, Tseng D, Hadi F, Omarjee S, Kishore K, Kent J, Kirkpatrick J, D'Santos C, Lawson M, Gertz J, Sikora MJ, McDonnell DP, Carroll JS, Polyak K, Oesterreich S, Lee AV. The EstroGene2.0 database for endocrine therapy response and resistance in breast cancer. NPJ Breast Cancer 2024; 10:106. [PMID: 39702552 PMCID: PMC11659402 DOI: 10.1038/s41523-024-00709-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 11/08/2024] [Indexed: 12/21/2024] Open
Abstract
Endocrine therapies targeting the estrogen receptor (ER/ESR1) are the cornerstone to treat ER-positive breast cancers patients, but resistance often limits their effectiveness. Notable progress has been made although the fragmented way data is reported has reduced their potential impact. Here, we introduce EstroGene2.0, an expanded database of its precursor 1.0 version. EstroGene2.0 focusses on response and resistance to endocrine therapies in breast cancer models. Incorporating multi-omic profiling of 361 experiments from 212 studies across 28 cell lines, a user-friendly browser offers comprehensive data visualization and metadata mining capabilities ( https://estrogeneii.web.app/ ). Taking advantage of the harmonized data collection, our follow-up meta-analysis revealed transcriptomic landscape and substantial diversity in response to different classes of ER modulators. Endocrine-resistant models exhibit a spectrum of transcriptomic alterations including a contra-directional shift in ER and interferon signalings, which is recapitulated clinically. Dissecting multiple ESR1-mutant cell models revealed the different clinical relevance of cell model engineering and identified high-confidence mutant-ER targets, such as NPY1R. These examples demonstrate how EstroGene2.0 helps investigate breast cancer's response to endocrine therapies and explore resistance mechanisms.
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Affiliation(s)
- Zheqi Li
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Fangyuan Chen
- School of Medicine, Tsinghua University, Beijing, China
- Women's Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Li Chen
- Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA
| | - Jiebin Liu
- Women's Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Medical Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Danielle Tseng
- Women's Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Fazal Hadi
- AstraZeneca, The Discovery Centre, Biomedical Campus, Cambridge, UK
| | - Soleilmane Omarjee
- Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Kamal Kishore
- Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Joshua Kent
- Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Joanna Kirkpatrick
- Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Clive D'Santos
- Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Mandy Lawson
- AstraZeneca, The Discovery Centre, Biomedical Campus, Cambridge, UK
| | - Jason Gertz
- Department of Oncological Sciences, University of Utah, Salt Lake City, UT, USA
| | - Matthew J Sikora
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Donald P McDonnell
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Jason S Carroll
- Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Kornelia Polyak
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Steffi Oesterreich
- Women's Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Adrian V Lee
- Women's Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
- Institute for Precision Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
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6
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Yan J, Yang A, Tu S. The relationship between keratin 18 and epithelial-derived tumors: as a diagnostic marker, prognostic marker, and its role in tumorigenesis. Front Oncol 2024; 14:1445978. [PMID: 39502314 PMCID: PMC11534658 DOI: 10.3389/fonc.2024.1445978] [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: 06/08/2024] [Accepted: 09/25/2024] [Indexed: 11/08/2024] Open
Abstract
As a structural protein, keratin is mainly expressed in epithelial cells and skin appendages to provide mechanical support and external resistance. The keratin family has a total of 54 members, which are divided into type I and type II. Two types of keratins connect to each other to form keratin intermediate filaments and participate in the construction of the cytoskeleton. K18 is a non-hair keratin, which is widely expressed in simple epithelial tissues with its partner, K8. Compared with mechanical support, K8/K18 pairs play more important roles in biological regulation, such as mediating anti-apoptosis, regulating cell cycle progression, and transmitting signals. Mutations in K18 can cause a variety of non-neoplastic diseases of the visceral epithelium. In addition, the expression levels of K18 are frequently altered in various epithelial-derived tumors, especially adenocarcinomas, which suggests that K18 may be involved in tumorigenesis. Due to the specific expression pattern of K18 in tumor tissues and its serum level reflecting tumor cell death, apply K18 to diagnose tumors and predict its prognosis have the potential to be simple and effective alternative methods. However, these potential roles of K18 in tumors have not been fully summarized. In this review, we focus on the relationship between K18 and epithelial-derived tumors, discuss the value of K18 as a diagnostic and prognostic marker, and summarize the interactions of K18 with various related proteins in tumorigenesis, with examples of simple epithelial tumors such as lung, breast, liver, and gastrointestinal cancers.
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Affiliation(s)
- Jiazhi Yan
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Aiwei Yang
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Shuo Tu
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
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7
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Verhoog NJD, Spies LML. The anti-aromatase and anti-estrogenic activity of plant products in the treatment of estrogen receptor-positive breast cancer. J Steroid Biochem Mol Biol 2024; 243:106581. [PMID: 38997071 DOI: 10.1016/j.jsbmb.2024.106581] [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: 11/09/2023] [Revised: 06/14/2024] [Accepted: 07/09/2024] [Indexed: 07/14/2024]
Abstract
Despite being the focal point of decades of research, female breast cancer (BC) continues to be one of the most lethal cancers in the world. Given that 80 % of all diagnosed BC cases are estrogen receptor-positive (ER+) with carcinogenesis driven by estrogen-ERα signalling, current standard of care (SOC) hormone therapies are geared towards modulating the function and expression levels of estrogen and its receptors, ERα and ERβ. Currently, aromatase inhibitors (AIs), selective ER modulators (SERMs) and selective ER degraders (SERDs) are clinically prescribed for the management and treatment of ER+ BC, with the anti-aromatase activity of AIs abrogating estrogen biosynthesis, while the anti-estrogenic SERMs and SERDs antagonise and degrade the ER, respectively. The use of SOC hormone therapies is, however, significantly hampered by the onset of severe side-effects and the development of resistance. Given that numerous studies have reported on the beneficial effects of plant compounds and/or extracts and the multiple pathways through which they target ER+ breast carcinogenesis, recent research has focused on the use of dietary chemopreventive agents for BC management. When combined with SOC treatments, several of these plant components and/or extracts have demonstrated improved efficacy and/or synergistic impact. Moreover, despite a lack of in vivo investigations, plant products are generally reported to have a lower side-effect profile than SOC therapies and are therefore thought to be a safer therapeutic choice. Thus, the current review summarizes the findings from the last five years regarding the anti-aromatase and anti-estrogenic activity of plant products, as well as their synergistic anti-ER+ BC effects in combination with SOC therapies.
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Affiliation(s)
| | - Lee-Maine Lorin Spies
- Department of Biochemistry, Stellenbosch University, Van de Byl Street, Stellenbosch, 7601, South Africa
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8
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Suba Z. Estrogen Regulated Genes Compel Apoptosis in Breast Cancer Cells, Whilst Stimulate Antitumor Activity in Peritumoral Immune Cells in a Janus-Faced Manner. Curr Oncol 2024; 31:4885-4907. [PMID: 39329990 PMCID: PMC11431267 DOI: 10.3390/curroncol31090362] [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: 07/13/2024] [Revised: 08/15/2024] [Accepted: 08/22/2024] [Indexed: 09/28/2024] Open
Abstract
Background: Breast cancer incidence and mortality exhibit a rising trend globally among both premenopausal and postmenopausal women, suggesting that there are serious errors in our preventive and therapeutic measures. Purpose: Providing a series of valuable, but misunderstood inventions highlighting the role of increasing estrogen signaling in prevention and therapy of breast cancer instead of its inhibition. Results: 1. Breast cells and breast cancer cells with germline BRCA1/2 mutations similarly show defects in liganded estrogen receptor (ER) signaling, demonstrating its role in genomic instability and cancer initiation. 2. In breast tumors, the increased expression of special receptor family maybe an effort for self-directed improvement of genomic defects, while the weakness or loss of receptors indicates a defect requiring medical repair. 3. ER overexpression in breast cancer cells is capable of strengthening estrogen signaling and DNA repair, while in ER negative tumors, HER2 overexpression tries to upregulate unliganded ER activation and genome stabilization. 4. ER-positive breast cancers responsive to endocrine therapy may show a compensatory ER overexpression resulting in a transient tumor response. Breast cancers non-responsive to antiestrogen treatment exhibit HER2-overexpression for compensating the complete inhibition of hormonal ER activation. 5. In breast tumors, somatic mutations serve upregulation of ER activation via liganded or unliganded pathway helping genome stabilization and apoptotic death. 6. The mutual communication between breast cancer and its inflammatory environment is a wonderful partnership among cells fighting for genome stabilization and apoptotic death of tumor. 7. In breast cancers, there is no resistance to genotoxic or immune blocker therapies, but rather, the nonresponsive tumor cells exhaust all compensatory possibilities against therapeutic damages. Conclusions: Understanding the behavior and ambition of breast cancer cells may achieve a turn in therapy via applying supportive care instead of genotoxic measures.
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Affiliation(s)
- Zsuzsanna Suba
- Department of Molecular Pathology, National Institute of Oncology, Ráth György Str. 7-9, H-1122 Budapest, Hungary
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9
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Zhang R, He Z, Shi Y, Sun X, Chen X, Wang G, Zhang Y, Gao P, Wu Y, Lu S, Duan J, Sun S, Yang N, Fan W, Zhao K, Yang B, Xia Y, Zhang Y, Zhang Y, Yin H. Amplification editing enables efficient and precise duplication of DNA from short sequence to megabase and chromosomal scale. Cell 2024; 187:3936-3952.e19. [PMID: 38936359 DOI: 10.1016/j.cell.2024.05.056] [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: 12/25/2023] [Revised: 03/24/2024] [Accepted: 05/31/2024] [Indexed: 06/29/2024]
Abstract
Duplication is a foundation of molecular evolution and a driver of genomic and complex diseases. Here, we develop a genome editing tool named Amplification Editing (AE) that enables programmable DNA duplication with precision at chromosomal scale. AE can duplicate human genomes ranging from 20 bp to 100 Mb, a size comparable to human chromosomes. AE exhibits activity across various cell types, encompassing diploid, haploid, and primary cells. AE exhibited up to 73.0% efficiency for 1 Mb and 3.4% for 100 Mb duplications, respectively. Whole-genome sequencing and deep sequencing of the junctions of edited sequences confirm the precision of duplication. AE can create chromosomal microduplications within disease-relevant regions in embryonic stem cells, indicating its potential for generating cellular and animal models. AE is a precise and efficient tool for chromosomal engineering and DNA duplication, broadening the landscape of precision genome editing from an individual genetic locus to the chromosomal scale.
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Affiliation(s)
- Ruiwen Zhang
- Departments of Urology and Laboratory Medicine, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, State Key Laboratory of Virology, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China; Department of Rheumatology and Immunology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
| | - Zhou He
- Departments of Urology and Laboratory Medicine, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, State Key Laboratory of Virology, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Yajing Shi
- Departments of Urology and Laboratory Medicine, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, State Key Laboratory of Virology, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Xiangkun Sun
- Departments of Urology and Laboratory Medicine, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, State Key Laboratory of Virology, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Xinyu Chen
- Departments of Urology and Laboratory Medicine, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, State Key Laboratory of Virology, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Guoquan Wang
- Departments of Urology and Laboratory Medicine, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, State Key Laboratory of Virology, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Yizhou Zhang
- Departments of Urology and Laboratory Medicine, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, State Key Laboratory of Virology, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Pan Gao
- Departments of Urology and Laboratory Medicine, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, State Key Laboratory of Virology, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Ying Wu
- Departments of Urology and Laboratory Medicine, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, State Key Laboratory of Virology, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Shuhan Lu
- Departments of Urology and Laboratory Medicine, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, State Key Laboratory of Virology, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Junyi Duan
- Departments of Urology and Laboratory Medicine, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, State Key Laboratory of Virology, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Shangwu Sun
- Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Na Yang
- Center for Gene Diagnosis and Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Wei Fan
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Kaitao Zhao
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan 430071, China
| | - Bei Yang
- Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Yuchen Xia
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan 430071, China
| | - Yan Zhang
- Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Ying Zhang
- Departments of Urology and Laboratory Medicine, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, State Key Laboratory of Virology, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China; Department of Rheumatology and Immunology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
| | - Hao Yin
- Departments of Urology and Laboratory Medicine, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, State Key Laboratory of Virology, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China.
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10
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Li Z, Chen F, Chen L, Liu J, Tseng D, Hadi F, Omarjee S, Kishore K, Kent J, Kirkpatrick J, D’Santos C, Lawson M, Gertz J, Sikora MJ, McDonnell DP, Carroll JS, Polyak K, Oesterreich S, Lee AV. EstroGene2.0: A multi-omic database of response to estrogens, ER-modulators, and resistance to endocrine therapies in breast cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.28.601163. [PMID: 39005294 PMCID: PMC11244912 DOI: 10.1101/2024.06.28.601163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
Endocrine therapies targeting the estrogen receptor (ER/ESR1) are the cornerstone to treat ER-positive breast cancers patients, but resistance often limits their effectiveness. Understanding the molecular mechanisms is thus key to optimize the existing drugs and to develop new ER-modulators. Notable progress has been made although the fragmented way data is reported has reduced their potential impact. Here, we introduce EstroGene2.0, an expanded database of its precursor 1.0 version. EstroGene2.0 focusses on response and resistance to endocrine therapies in breast cancer models. Incorporating multi-omic profiling of 361 experiments from 212 studies across 28 cell lines, a user-friendly browser offers comprehensive data visualization and metadata mining capabilities (https://estrogeneii.web.app/). Taking advantage of the harmonized data collection, our follow-up meta-analysis revealed substantial diversity in response to different classes of ER-modulators including SERMs, SERDs, SERCA and LDD/PROTAC. Notably, endocrine resistant models exhibit a spectrum of transcriptomic alterations including a contra-directional shift in ER and interferon signaling, which is recapitulated clinically. Furthermore, dissecting multiple ESR1-mutant cell models revealed the different clinical relevance of genome-edited versus ectopic overexpression model engineering and identified high-confidence mutant-ER targets, such as NPY1R. These examples demonstrate how EstroGene2.0 helps investigate breast cancer's response to endocrine therapies and explore resistance mechanisms.
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Affiliation(s)
- Zheqi Li
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Fangyuan Chen
- School of Medicine, Tsinghua University, Beijing, China
- Women’s Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh PA, USA
| | - Li Chen
- Computational Biology Department, Carnegie Mellon University, Pittsburgh PA, USA
| | - Jiebin Liu
- Women’s Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh PA, USA
- Medical Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Danielle Tseng
- Women’s Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh PA, USA
| | | | - Soleilmane Omarjee
- Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Kamal Kishore
- Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Joshua Kent
- Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Joanna Kirkpatrick
- Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Clive D’Santos
- Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK
| | | | - Jason Gertz
- Department of Oncological Sciences, University of Utah, Salt Lake City, UT, USA
| | - Matthew J. Sikora
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Donald P. McDonnell
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Jason S. Carroll
- Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Kornelia Polyak
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Steffi Oesterreich
- Women’s Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh PA, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh PA, USA
| | - Adrian V. Lee
- Women’s Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh PA, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh PA, USA
- Institute for Precision Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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11
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Valentín López JC, Lange CA, Dehm SM. Androgen receptor and estrogen receptor variants in prostate and breast cancers. J Steroid Biochem Mol Biol 2024; 241:106522. [PMID: 38641298 PMCID: PMC11139604 DOI: 10.1016/j.jsbmb.2024.106522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 03/23/2024] [Accepted: 04/14/2024] [Indexed: 04/21/2024]
Abstract
The androgen receptor (AR) and estrogen receptor alpha (ERα) are steroid receptor transcription factors with critical roles in the development and progression of prostate and breast cancers. Advances in the understanding of mechanisms underlying the ligand-dependent activation of these transcription factors have contributed to the development of small molecule inhibitors that block AR and ERα actions. These inhibitors include competitive antagonists and degraders that directly bind the ligand binding domains of these receptors, luteinizing hormone releasing hormone (LHRH) analogs that suppress gonadal synthesis of testosterone or estrogen, and drugs that block specific enzymes required for biosynthesis of testosterone or estrogen. However, resistance to these therapies is frequent, and is often driven by selection for tumor cells with alterations in the AR or ESR1 genes and/or alternatively spliced AR or ESR1 mRNAs that encode variant forms AR or ERα. While most investigations involving AR have been within the context of prostate cancer, and the majority of investigations involving ERα have been within the context of breast cancer, important roles for AR have been elucidated in breast cancer, and important roles for ERα have been elucidated in prostate cancer. Here, we will discuss the roles of AR and ERα in breast and prostate cancers, outline the effects of gene- and mRNA-level alterations in AR and ESR1 on progression of these diseases, and identify strategies that are being developed to target these alterations therapeutically.
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Affiliation(s)
| | - Carol A Lange
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Department of Medicine-Hematology, Oncology & Transplantation, University of Minnesota, Minneapolis, MN, USA
| | - Scott M Dehm
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA; Department of Urology, University of Minnesota, Minneapolis, MN, USA.
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12
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Hancock GR, Gertz J, Jeselsohn R, Fanning SW. Estrogen Receptor Alpha Mutations, Truncations, Heterodimers, and Therapies. Endocrinology 2024; 165:bqae051. [PMID: 38643482 PMCID: PMC11075793 DOI: 10.1210/endocr/bqae051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 04/02/2024] [Accepted: 04/17/2024] [Indexed: 04/23/2024]
Abstract
Annual breast cancer (BCa) deaths have declined since its apex in 1989 concomitant with widespread adoption of hormone therapies that target estrogen receptor alpha (ERα), the prominent nuclear receptor expressed in ∼80% of BCa. However, up to ∼50% of patients who are ER+ with high-risk disease experience post endocrine therapy relapse and metastasis to distant organs. The vast majority of BCa mortality occurs in this setting, highlighting the inadequacy of current therapies. Genomic abnormalities to ESR1, the gene encoding ERα, emerge under prolonged selective pressure to enable endocrine therapy resistance. These genetic lesions include focal gene amplifications, hotspot missense mutations in the ligand binding domain, truncations, fusions, and complex interactions with other nuclear receptors. Tumor cells utilize aberrant ERα activity to proliferate, spread, and evade therapy in BCa as well as other cancers. Cutting edge studies on ERα structural and transcriptional relationships are being harnessed to produce new therapies that have shown benefits in patients with ESR1 hotspot mutations. In this review we discuss the history of ERα, current research unlocking unknown aspects of ERα signaling including the structural basis for receptor antagonism, and future directions of ESR1 investigation. In addition, we discuss the development of endocrine therapies from their inception to present day and survey new avenues of drug development to improve pharmaceutical profiles, targeting, and efficacy.
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Affiliation(s)
- Govinda R Hancock
- Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL 60513, USA
| | - Jason Gertz
- Department of Oncological Sciences, Huntsman Cancer Center, University of Utah, Salt Lake City, UT 84112, USA
| | - Rinath Jeselsohn
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Sean W Fanning
- Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL 60513, USA
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13
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Suba Z. DNA Damage Responses in Tumors Are Not Proliferative Stimuli, but Rather They Are DNA Repair Actions Requiring Supportive Medical Care. Cancers (Basel) 2024; 16:1573. [PMID: 38672654 PMCID: PMC11049279 DOI: 10.3390/cancers16081573] [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: 03/05/2024] [Revised: 04/05/2024] [Accepted: 04/16/2024] [Indexed: 04/28/2024] Open
Abstract
BACKGROUND In tumors, somatic mutagenesis presumably drives the DNA damage response (DDR) via altered regulatory pathways, increasing genomic instability and proliferative activity. These considerations led to the standard therapeutic strategy against cancer: the disruption of mutation-activated DNA repair pathways of tumors. PURPOSE Justifying that cancer cells are not enemies to be killed, but rather that they are ill human cells which have the remnants of physiologic regulatory pathways. RESULTS 1. Genomic instability and cancer development may be originated from a flaw in estrogen signaling rather than excessive estrogen signaling; 2. Healthy cells with genomic instability exhibit somatic mutations, helping DNA restitution; 3. Somatic mutations in tumor cells aim for the restoration of DNA damage, rather than further genomic derangement; 4. In tumors, estrogen signaling drives the pathways of DNA stabilization, leading to apoptotic death; 5. In peritumoral cellular infiltration, the genomic damage of the tumor induces inflammatory cytokine secretion and increased estrogen synthesis. In the inflammatory cells, an increased growth factor receptor (GFR) signaling confers the unliganded activation of estrogen receptors (ERs); 6. In breast cancer cells responsive to genotoxic therapy, constitutive mutations help the upregulation of estrogen signaling and consequential apoptosis. In breast tumors non-responsive to genotoxic therapy, the possibilities for ER activation via either liganded or unliganded pathways are exhausted, leading to farther genomic instability and unrestrained proliferation. CONCLUSIONS Understanding the real character and behavior of human tumors at the molecular level suggests that we should learn the genome repairing methods of tumors and follow them by supportive therapy, rather than provoking additional genomic damages.
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Affiliation(s)
- Zsuzsanna Suba
- Department of Molecular Pathology, National Institute of Oncology, Ráth György Str. 7-9, H-1122 Budapest, Hungary
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14
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Guglielmi G, Del Re M, Gol LS, Bengala C, Danesi R, Fogli S. Pharmacological insights on novel oral selective estrogen receptor degraders in breast cancer. Eur J Pharmacol 2024; 969:176424. [PMID: 38402929 DOI: 10.1016/j.ejphar.2024.176424] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 02/08/2024] [Accepted: 02/14/2024] [Indexed: 02/27/2024]
Abstract
The therapeutic landscape of estrogen receptor (ER)-positive breast cancer includes endocrine treatments with aromatase inhibitors (AIs), selective estrogen receptor modulators (SERMs), and selective estrogen receptor degraders (SERDs). Fulvestrant is the first approved SERD with proven efficacy and good tolerability in clinical practice. However, drug resistance, low receptor affinity, and parental administration stimulated the search for new oral SERDs opening a new therapeutic era in ER + breast cancer. Elacestrant is an orally bioavailable SERD that has been recently approved by the FDA for postmenopausal women with ER+, human epidermal growth factor receptor 2-negative (HER2-), estrogen receptor 1 (ESR1)-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. Other molecules of the same class currently tested in clinical trials are amcenestrant, giredestrant, camizestrant, and imlunestrant. The current review article offers a detailed pharmacological perspective of this emerging drug class, which may help with their possible future clinical applications.
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Affiliation(s)
- Giorgio Guglielmi
- Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Marzia Del Re
- Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Leila Sadeghi Gol
- Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Carmelo Bengala
- Clinical Oncology Unit 1, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Romano Danesi
- Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; Department of Oncology and Hemato-Oncology, University of Milano, Milano, Italy.
| | - Stefano Fogli
- Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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15
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Abstract
Molecular abnormalities that shape human neoplasms dissociate their phenotypic landscape from that of the healthy counterpart. Through the lens of a microscope, tumour pathology optically captures such aberrations projected onto a tissue slide and has categorized human epithelial neoplasms into distinct histological subtypes based on the diverse morphogenetic and molecular programmes that they manifest. Tumour histology often reflects tumour aggressiveness, patient prognosis and therapeutic vulnerability, and thus has been used as a de facto diagnostic tool and for making clinical decisions. However, it remains elusive how the diverse histological subtypes arise and translate into pleiotropic biological phenotypes. Molecular analysis of clinical tumour tissues and their culture, including patient-derived organoids, and add-back genetic reconstruction of tumorigenic pathways using gene engineering in culture models and rodents further elucidated molecular mechanisms that underlie morphological variations. Such mechanisms include genetic mutations and epigenetic alterations in cellular identity codes that erode hard-wired morphological programmes and histologically digress tumours from the native tissues. Interestingly, tumours acquire the ability to grow independently of the niche-driven stem cell ecosystem along with these morphological alterations, providing a biological rationale for histological diversification during tumorigenesis. This Review comprehensively summarizes our current understanding of such plasticity in the histological and lineage commitment fostered cooperatively by molecular alterations and the tumour environment, and describes basic and clinical implications for future cancer therapy.
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Affiliation(s)
- Masayuki Fujii
- Department of Integrated Medicine and Biochemistry, Keio University School of Medicine, Tokyo, Japan.
| | - Shigeki Sekine
- Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
| | - Toshiro Sato
- Department of Integrated Medicine and Biochemistry, Keio University School of Medicine, Tokyo, Japan.
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16
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Kumar S, Pauline G, Vindal V. NetVA: an R package for network vulnerability and influence analysis. J Biomol Struct Dyn 2024:1-12. [PMID: 38234040 DOI: 10.1080/07391102.2024.2303607] [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: 08/28/2023] [Accepted: 01/04/2024] [Indexed: 01/19/2024]
Abstract
In biological network analysis, identifying key molecules plays a decisive role in the development of potential diagnostic and therapeutic candidates. Among various approaches of network analysis, network vulnerability analysis is quite important, as it assesses significant associations between topological properties and the functional essentiality of a network. Similarly, some node centralities are also used to screen out key molecules. Among these node centralities, escape velocity centrality (EVC), and its extended version (EVC+) outperform others, viz., Degree, Betweenness, and Clustering coefficient. Keeping this in mind, we aimed to develop a first-of-its-kind R package named NetVA, which analyzes networks to identify key molecular players (individual proteins and protein pairs/triplets) through network vulnerability and EVC+-based approaches. To demonstrate the application and relevance of our package in network analysis, previously published and publicly available protein-protein interactions (PPIs) data of human breast cancer were analyzed. This resulted in identifying some most important proteins. These included essential proteins, non-essential proteins, hubs, and bottlenecks, which play vital roles in breast cancer development. Thus, the NetVA package, available at https://github.com/kr-swapnil/NetVA with a detailed tutorial to download and use, assists in predicting potential candidates for therapeutic and diagnostic purposes by exploring various topological features of a disease-specific PPIs network.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Swapnil Kumar
- Department of Biotechnology & Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Grace Pauline
- Department of Biotechnology & Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Vaibhav Vindal
- Department of Biotechnology & Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, India
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17
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Sharma K, Panwar U, Madhavi M, Joshi I, Chopra I, Soni L, Khan A, Bhrdwaj A, Parihar AS, Mohan VP, Prajapati L, Sharma R, Agrawal S, Hussain T, Nayarisseri A, Singh SK. Unveiling the ESR1 Conformational Stability and Screening Potent Inhibitors for Breast Cancer Treatment. Med Chem 2024; 20:352-368. [PMID: 37929724 DOI: 10.2174/0115734064256978231024062937] [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: 05/08/2023] [Revised: 09/21/2023] [Accepted: 09/28/2023] [Indexed: 11/07/2023]
Abstract
BACKGROUND The current study recognizes the significance of estrogen receptor alpha (ERα) as a member of the nuclear receptor protein family, which holds a central role in the pathophysiology of breast cancer. ERα serves as a valuable prognostic marker, with its established relevance in predicting disease outcomes and treatment responses. METHODS In this study, computational methods are utilized to search for suitable drug-like compounds that demonstrate analogous ligand binding kinetics to ERα. RESULTS Docking-based simulation screened out the top 5 compounds - ZINC13377936, NCI35753, ZINC35465238, ZINC14726791, and NCI663569 against the targeted protein. Further, their dynamics studies reveal that the compounds ZINC13377936 and NCI35753 exhibit the highest binding stability and affinity. CONCLUSION Anticipating the competitive inhibition of ERα protein expression in breast cancer, we envision that both ZINC13377936 and NCI35753 compounds hold substantial promise as potential therapeutic agents. These candidates warrant thorough consideration for rigorous In vitro and In vivo evaluations within the context of clinical trials. The findings from this current investigation carry significant implications for the advancement of future diagnostic and therapeutic approaches for breast cancer.
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Affiliation(s)
- Khushboo Sharma
- In silico Research Laboratory, Eminent Biosciences, 91, Sector A, Mahalakshmi Nagar, Indore - 452010, Madhya Pradesh, India
- Computer Aided Drug Designing and Molecular Modelling Lab, Department of Bioinformatics, Alagappa University, Karaikudi-630 003, Tamil Nadu, India
| | - Umesh Panwar
- Computer Aided Drug Designing and Molecular Modelling Lab, Department of Bioinformatics, Alagappa University, Karaikudi-630 003, Tamil Nadu, India
| | - Maddala Madhavi
- Department of Zoology, Osmania University, Hyderabad - 500007, Telangana State, India
| | - Isha Joshi
- In silico Research Laboratory, Eminent Biosciences, 91, Sector A, Mahalakshmi Nagar, Indore - 452010, Madhya Pradesh, India
| | - Ishita Chopra
- In silico Research Laboratory, Eminent Biosciences, 91, Sector A, Mahalakshmi Nagar, Indore - 452010, Madhya Pradesh, India
- School of Medicine and Health Sciences, The George Washington University, Ross Hall, 2300 Eye Street, NW Washington, D.C. - 20037, USA
| | - Lovely Soni
- In silico Research Laboratory, Eminent Biosciences, 91, Sector A, Mahalakshmi Nagar, Indore - 452010, Madhya Pradesh, India
| | - Arshiya Khan
- In silico Research Laboratory, Eminent Biosciences, 91, Sector A, Mahalakshmi Nagar, Indore - 452010, Madhya Pradesh, India
| | - Anushka Bhrdwaj
- In silico Research Laboratory, Eminent Biosciences, 91, Sector A, Mahalakshmi Nagar, Indore - 452010, Madhya Pradesh, India
| | - Abhyuday Singh Parihar
- In silico Research Laboratory, Eminent Biosciences, 91, Sector A, Mahalakshmi Nagar, Indore - 452010, Madhya Pradesh, India
| | - Vineeth Pazharathu Mohan
- In silico Research Laboratory, Eminent Biosciences, 91, Sector A, Mahalakshmi Nagar, Indore - 452010, Madhya Pradesh, India
- Department of Biosciences, School of Science and Technology, Nottingham Trent University Clifton Campus, Nottingham, NG11 8NS, United Kingdom
| | - Leena Prajapati
- In silico Research Laboratory, Eminent Biosciences, 91, Sector A, Mahalakshmi Nagar, Indore - 452010, Madhya Pradesh, India
| | - Rashmi Sharma
- In silico Research Laboratory, Eminent Biosciences, 91, Sector A, Mahalakshmi Nagar, Indore - 452010, Madhya Pradesh, India
| | - Shweta Agrawal
- In silico Research Laboratory, Eminent Biosciences, 91, Sector A, Mahalakshmi Nagar, Indore - 452010, Madhya Pradesh, India
| | - Tajamul Hussain
- Research Chair for Biomedical Applications of Nanomaterials, Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia
- Center of Excellence in Biotechnology Research, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Anuraj Nayarisseri
- In silico Research Laboratory, Eminent Biosciences, 91, Sector A, Mahalakshmi Nagar, Indore - 452010, Madhya Pradesh, India
- Computer Aided Drug Designing and Molecular Modelling Lab, Department of Bioinformatics, Alagappa University, Karaikudi-630 003, Tamil Nadu, India
- Research Chair for Biomedical Applications of Nanomaterials, Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia
- Bioinformatics Research Laboratory, LeGene Biosciences Pvt Ltd., Indore - 452010, Madhya Pradesh, India
| | - Sanjeev Kumar Singh
- Computer Aided Drug Designing and Molecular Modelling Lab, Department of Bioinformatics, Alagappa University, Karaikudi-630 003, Tamil Nadu, India
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18
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Kim K, Kim S, Ahn T, Kim H, Shin SJ, Choi CH, Park S, Kim YB, No JH, Suh DH. A differential diagnosis between uterine leiomyoma and leiomyosarcoma using transcriptome analysis. BMC Cancer 2023; 23:1215. [PMID: 38066476 PMCID: PMC10709939 DOI: 10.1186/s12885-023-11394-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 09/11/2023] [Indexed: 12/18/2023] Open
Abstract
BACKGROUND The objective of this study was to estimate the accuracy of transcriptome-based classifier in differential diagnosis of uterine leiomyoma and leiomyosarcoma. We manually selected 114 normal uterine tissue and 31 leiomyosarcoma samples from publicly available transcriptome data in UCSC Xena as training/validation sets. We developed pre-processing procedure and gene selection method to sensitively find genes of larger variance in leiomyosarcoma than normal uterine tissues. Through our method, 17 genes were selected to build transcriptome-based classifier. The prediction accuracies of deep feedforward neural network (DNN), support vector machine (SVM), random forest (RF), and gradient boosting (GB) models were examined. We interpret the biological functionality of selected genes via network-based analysis using GeneMANIA. To validate the performance of trained model, we additionally collected 35 clinical samples of leiomyosarcoma and leiomyoma as a test set (18 + 17 as 1st and 2nd test sets). RESULTS We discovered genes expressed in a highly variable way in leiomyosarcoma while these genes are expressed in a conserved way in normal uterine samples. These genes were mainly associated with DNA replication. As gene selection and model training were made in leiomyosarcoma and uterine normal tissue, proving discriminant of ability between leiomyosarcoma and leiomyoma is necessary. Thus, further validation of trained model was conducted in newly collected clinical samples of leiomyosarcoma and leiomyoma. The DNN classifier performed sensitivity 0.88, 0.77 (8/9, 7/9) while the specificity 1.0 (8/8, 8/8) in two test data set supporting that the selected genes in conjunction with DNN classifier are well discriminating the difference between leiomyosarcoma and leiomyoma in clinical sample. CONCLUSION The transcriptome-based classifier accurately distinguished uterine leiomyosarcoma from leiomyoma. Our method can be helpful in clinical practice through the biopsy of sample in advance of surgery. Identification of leiomyosarcoma let the doctor avoid of laparoscopic surgery, thus it minimizes un-wanted tumor spread.
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Affiliation(s)
- Kidong Kim
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Sarah Kim
- Department of Life Science, Handong Global University, Pohang, Republic of Korea
| | - TaeJin Ahn
- Department of Life Science, Handong Global University, Pohang, Republic of Korea.
| | - Hyojin Kim
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - So-Jin Shin
- Department of Gynecology and Obstetrics, School of Medicine, Keimyung University, Daegu, Republic of Korea
| | - Chel Hun Choi
- Department of Obstetrics and Gynecology, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sungmin Park
- Department of Life Science, Handong Global University, Pohang, Republic of Korea
| | - Yong-Beom Kim
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Jae Hong No
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Dong Hoon Suh
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
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19
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Wang R, Gou Y, Tang M, Wang K, He H, Yang J, Yang Y, Jing Y, Tang Q. A mutator-derived prognostic eRNA signature provides insight into the pathogenesis of breast cancer. Exp Cell Res 2023; 431:113754. [PMID: 37611728 DOI: 10.1016/j.yexcr.2023.113754] [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: 10/18/2022] [Revised: 07/23/2023] [Accepted: 08/11/2023] [Indexed: 08/25/2023]
Abstract
Abundant evidence suggests that enhancer RNA (eRNA) is closely related to tumorigenesis, and the role of eRNA transcription in promoting genomic instability in cancers is gradually unveiled. However, research on the evaluation of the prognostic value and molecular mechanisms of genomic instability associated eRNAs in breast cancer is long overdue. Here, we integratively analyzed eRNA expression and somatic mutation profiles in breast cancer genome. We identified genomic instability associated eRNAs and developed a prognostic signature based on these eRNAs with the area under the curve (AUC) around 0.8 at 9-year survival. We further found the prognostic value of this signature is independent of common clinical factors and is better than TP53 status. Higher expression of genomic instability associated genes in the high-risk group was observed, suggesting that this eRNA signature may serve as an indicator of genomic instability in breast cancer. We found prognostic eRNA co-expressed genes are mainly enriched in Gene set 'Breast Cancer 8P12-P11 Amplicon', Gene set 'Metabolism of lipids' and GO process 'Ubiquitin protein ligase binding'. Furthermore, 11 eRNA-signature regulated genes are identified by assessing promoter-enhancer interaction. Among these genes, F11R, BHLHE40, and NECTIN4 are previously reported oncogenes and EGOT is a tumor suppressor gene, indicating the direct roles of eRNAs in tumorigenesis.
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Affiliation(s)
- Rui Wang
- Live-stock and Poultry Multi-omics Key Laboratory of Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China; Animal Breeding and Genetics Key Laboratory of Sichuan Province, Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, 611130, China
| | - Yuwei Gou
- Live-stock and Poultry Multi-omics Key Laboratory of Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China; Animal Breeding and Genetics Key Laboratory of Sichuan Province, Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, 611130, China
| | - Minzi Tang
- China Certification & Inspection Group Sichuan CO., LTD, Chengdu, 610063, China
| | - Kai Wang
- Live-stock and Poultry Multi-omics Key Laboratory of Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China; Animal Breeding and Genetics Key Laboratory of Sichuan Province, Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, 611130, China
| | - Hengdong He
- Live-stock and Poultry Multi-omics Key Laboratory of Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China; Animal Breeding and Genetics Key Laboratory of Sichuan Province, Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, 611130, China
| | - Jing Yang
- Live-stock and Poultry Multi-omics Key Laboratory of Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China; Animal Breeding and Genetics Key Laboratory of Sichuan Province, Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, 611130, China
| | - Yuan Yang
- Live-stock and Poultry Multi-omics Key Laboratory of Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China; Animal Breeding and Genetics Key Laboratory of Sichuan Province, Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, 611130, China
| | - Yunhan Jing
- Live-stock and Poultry Multi-omics Key Laboratory of Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China; Animal Breeding and Genetics Key Laboratory of Sichuan Province, Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, 611130, China
| | - Qianzi Tang
- Live-stock and Poultry Multi-omics Key Laboratory of Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China; Animal Breeding and Genetics Key Laboratory of Sichuan Province, Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, 611130, China.
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20
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Ouyang D, Liang Y, Li L, Ai N, Lu S, Yu M, Liu X, Xie S. Integration of multi-omics data using adaptive graph learning and attention mechanism for patient classification and biomarker identification. Comput Biol Med 2023; 164:107303. [PMID: 37586201 DOI: 10.1016/j.compbiomed.2023.107303] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 07/08/2023] [Accepted: 07/28/2023] [Indexed: 08/18/2023]
Abstract
With the rapid development and accumulation of high-throughput sequencing technology and omics data, many studies have conducted a more comprehensive understanding of human diseases from a multi-omics perspective. Meanwhile, graph-based methods have been widely used to process multi-omics data due to its powerful expressive ability. However, most existing graph-based methods utilize fixed graphs to learn sample embedding representations, which often leads to sub-optimal results. Furthermore, treating embedding representations of different omics equally usually cannot obtain more reasonable integrated information. In addition, the complex correlation between omics is not fully taken into account. To this end, we propose an end-to-end interpretable multi-omics integration method, named MOGLAM, for disease classification prediction. Dynamic graph convolutional network with feature selection is first utilized to obtain higher quality omic-specific embedding information by adaptively learning the graph structure and discover important biomarkers. Then, multi-omics attention mechanism is applied to adaptively weight the embedding representations of different omics, thereby obtaining more reasonable integrated information. Finally, we propose omic-integrated representation learning to capture complex common and complementary information between omics while performing multi-omics integration. Experimental results on three datasets show that MOGLAM achieves superior performance than other state-of-the-art multi-omics integration methods. Moreover, MOGLAM can identify important biomarkers from different omics data types in an end-to-end manner.
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Affiliation(s)
- Dong Ouyang
- Peng Cheng Laboratory, Shenzhen, 518055, China; School of Computer Science and Engineering, Faculty of Innovation Engineering, Macau University of Science and Technology, 999078, Macao Special Administrative Region of China
| | - Yong Liang
- Peng Cheng Laboratory, Shenzhen, 518055, China.
| | - Le Li
- School of Computer Science and Engineering, Faculty of Innovation Engineering, Macau University of Science and Technology, 999078, Macao Special Administrative Region of China
| | - Ning Ai
- School of Computer Science and Engineering, Faculty of Innovation Engineering, Macau University of Science and Technology, 999078, Macao Special Administrative Region of China
| | - Shanghui Lu
- School of Computer Science and Engineering, Faculty of Innovation Engineering, Macau University of Science and Technology, 999078, Macao Special Administrative Region of China
| | - Mingkun Yu
- School of Computer Science and Engineering, Faculty of Innovation Engineering, Macau University of Science and Technology, 999078, Macao Special Administrative Region of China
| | - Xiaoying Liu
- Computer Engineering Technical College, Guangdong Polytechnic of Science and Technology, Zhuhai, 519090, China
| | - Shengli Xie
- Guangdong-HongKong-Macao Joint Laboratory for Smart Discrete Manufacturing, Guangzhou, 510000, China
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21
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Karimi Taheri M, Ghanbari S, Gholipour A, Givi T, Sadeghizadeh M. LINC01116 affects patient survival differently and is dissimilarly expressed in ER+ and ER- breast cancer samples. Cancer Rep (Hoboken) 2023; 6:e1848. [PMID: 37321964 PMCID: PMC10432450 DOI: 10.1002/cnr2.1848] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/18/2023] [Accepted: 06/05/2023] [Indexed: 06/17/2023] Open
Abstract
BACKGROUND Breast cancer is the most commonly detected cancer and one of the leading causes of cancer mortality. Emerging evidence supports that aberrant expression of lncRNAs is correlated with tumor progression and various aspects of tumor development. AIM This study aimed to evaluate the expression pattern of LINC01116 in breast cancer tissues and investigate the impact of LINC01116 on patients' survival. METHODS AND RESULTS Microarray and qRT-PCR data analysis were performed, and the KM-plotter database was used in this study. In addition, the gain of function approach was performed to examine the effect of LINC01116 on breast cancer cells in-vitro. The results exhibited that LINC01116 is meaningfully upregulated in the ER+ tumor specimens compared to the ER- ones. Also, relative to normal tissues, the expression of LINC01116 in ER+ and ER- tumor tissues significantly increased and decreased, respectively. ROC curve analysis revealed the power of LINC01116 in distinguishing ER+ from ER- samples. Additionally, the Kaplan-Meier survival analysis showed that the LINC01116 expression positively correlates with survival probability in all as well as ER+ patients. However, this correlation was negative in ER- patients. Furthermore, our results showed that the overexpression of LINC01116 induces TGF-β signaling in ER- cells (MDA-MB-231), and microarray data analysis revealed that LINC01116 is significantly upregulated in 17β-Estradiol treated MCF7 cells. CONCLUSION In conclusion, our results suggest that LINC01116 can be a potential biomarker in distinguishing ER+ and ER- tissues and has different effects on patients' survival based on ER status by affecting TGF-β and ER signaling.
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Affiliation(s)
| | - Sogol Ghanbari
- Molecular Genetics DepartmentBiological Sciences Faculty, Tarbiat Modares UniversityTehranIran
| | - Akram Gholipour
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research CenterIran University of Medical SciencesTehranIran
| | - Taraneh Givi
- Molecular Genetics DepartmentBiological Sciences Faculty, Tarbiat Modares UniversityTehranIran
| | - Majid Sadeghizadeh
- Molecular Genetics DepartmentBiological Sciences Faculty, Tarbiat Modares UniversityTehranIran
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22
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Li L, Duns GJ, Dessie W, Cao Z, Ji X, Luo X. Recent advances in peptide-based therapeutic strategies for breast cancer treatment. Front Pharmacol 2023; 14:1052301. [PMID: 36794282 PMCID: PMC9922721 DOI: 10.3389/fphar.2023.1052301] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 01/19/2023] [Indexed: 01/31/2023] Open
Abstract
Breast cancer is the leading cause of cancer-related fatalities in female worldwide. Effective therapies with low side effects for breast cancer treatment and prevention are, accordingly, urgently required. Targeting anticancer materials, breast cancer vaccines and anticancer drugs have been studied for many years to decrease side effects, prevent breast cancer and suppress tumors, respectively. There are abundant evidences to demonstrate that peptide-based therapeutic strategies, coupling of good safety and adaptive functionalities are promising for breast cancer therapy. In recent years, peptide-based vectors have been paid attention in targeting breast cancer due to their specific binding to corresponding receptors overexpressed in cell. To overcome the low internalization, cell penetrating peptides (CPPs) could be selected to increase the penetration due to the electrostatic and hydrophobic interactions between CPPs and cell membranes. Peptide-based vaccines are at the forefront of medical development and presently, 13 types of main peptide vaccines for breast cancer are being studied on phase III, phase II, phase I/II and phase I clinical trials. In addition, peptide-based vaccines including delivery vectors and adjuvants have been implemented. Many peptides have recently been used in clinical treatments for breast cancer. These peptides show different anticancer mechanisms and some novel peptides could reverse the resistance of breast cancer to susceptibility. In this review, we will focus on current studies of peptide-based targeting vectors, CPPs, peptide-based vaccines and anticancer peptides for breast cancer therapy and prevention.
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Affiliation(s)
- Ling Li
- Hunan Engineering Technology Research Center for Comprehensive Development and Utilization of Biomass Resources, College of Chemistry and Bioengineering, Hunan University of Science and Engineering, Yongzhou, China
| | - Gregory J. Duns
- Hunan Engineering Technology Research Center for Comprehensive Development and Utilization of Biomass Resources, College of Chemistry and Bioengineering, Hunan University of Science and Engineering, Yongzhou, China
| | - Wubliker Dessie
- Hunan Engineering Technology Research Center for Comprehensive Development and Utilization of Biomass Resources, College of Chemistry and Bioengineering, Hunan University of Science and Engineering, Yongzhou, China
| | - Zhenmin Cao
- Hunan Engineering Technology Research Center for Comprehensive Development and Utilization of Biomass Resources, College of Chemistry and Bioengineering, Hunan University of Science and Engineering, Yongzhou, China
| | - Xiaoyuan Ji
- Academy of Medical Engineering and Translational Medicine, Medical College, Tianjin University, Tianjin, China
| | - Xiaofang Luo
- Hunan Engineering Technology Research Center for Comprehensive Development and Utilization of Biomass Resources, College of Chemistry and Bioengineering, Hunan University of Science and Engineering, Yongzhou, China
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23
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Control of protein stability by post-translational modifications. Nat Commun 2023; 14:201. [PMID: 36639369 PMCID: PMC9839724 DOI: 10.1038/s41467-023-35795-8] [Citation(s) in RCA: 253] [Impact Index Per Article: 126.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 01/02/2023] [Indexed: 01/15/2023] Open
Abstract
Post-translational modifications (PTMs) can occur on specific amino acids localized within regulatory domains of target proteins, which control a protein's stability. These regions, called degrons, are often controlled by PTMs, which act as signals to expedite protein degradation (PTM-activated degrons) or to forestall degradation and stabilize a protein (PTM-inactivated degrons). We summarize current knowledge of the regulation of protein stability by various PTMs. We aim to display the variety and breadth of known mechanisms of regulation as well as highlight common themes in PTM-regulated degrons to enhance potential for identifying novel drug targets where druggable targets are currently lacking.
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24
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Ferrando L, Vingiani A, Garuti A, Vernieri C, Belfiore A, Agnelli L, Dagrada G, Ivanoiu D, Bonizzi G, Munzone E, Lippolis L, Dameri M, Ravera F, Colleoni M, Viale G, Magnani L, Ballestrero A, Zoppoli G, Pruneri G. ESR1 gene amplification and MAP3K mutations are selected during adjuvant endocrine therapies in relapsing Hormone Receptor-positive, HER2-negative breast cancer (HR+ HER2- BC). PLoS Genet 2023; 19:e1010563. [PMID: 36595552 PMCID: PMC9839248 DOI: 10.1371/journal.pgen.1010563] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 01/13/2023] [Accepted: 12/08/2022] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Previous studies have provided a comprehensive picture of genomic alterations in primary and metastatic Hormone Receptor (HR)-positive, Human Epidermal growth factor Receptor 2 (HER2)-negative breast cancer (HR+ HER2- BC). However, the evolution of the genomic landscape of HR+ HER2- BC during adjuvant endocrine therapies (ETs) remains poorly investigated. METHODS AND FINDINGS We performed a genomic characterization of surgically resected HR+ HER2- BC patients relapsing during or at the completion of adjuvant ET. Using a customized panel, we comprehensively evaluated gene mutations and copy number variation (CNV) in paired primary and metastatic specimens. After retrieval and quality/quantity check of tumor specimens from an original cohort of 204 cases, 74 matched tumor samples were successfully evaluated for DNA mutations and CNV analysis. Along with previously reported genomic alterations, including PIK3CA, TP53, CDH1, GATA3 and ESR1 mutations/deletions, we found that ESR1 gene amplification (confirmed by FISH) and MAP3K mutations were enriched in metastatic lesions as compared to matched primary tumors. These alterations were exclusively found in patients treated with adjuvant aromatase inhibitors or LHRH analogs plus tamoxifen, but not in patients treated with tamoxifen alone. Patients with tumors bearing MAP3K mutations in metastatic lesions had significantly worse distant relapse-free survival (hazard ratio [HR] 3.4, 95% CI 1.52-7.70, p value 0.003) and worse overall survival (HR 5.2, 95% CI 2.10-12.8, p-value < 0.001) independently of other clinically relevant patient- and tumor-related variables. CONCLUSIONS ESR1 amplification and activating MAP3K mutations are potential drivers of acquired resistance to adjuvant ETs employing estrogen deprivation in HR+ HER2- BC. MAP3K mutations are associated with worse prognosis in patients with metastatic disease.
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Affiliation(s)
| | - Andrea Vingiani
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Anna Garuti
- IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Claudio Vernieri
- Department of Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- IFOM, The FIRC Institute of Molecular Oncology, Milan, Italy
| | - Antonino Belfiore
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Luca Agnelli
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Gianpaolo Dagrada
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Diana Ivanoiu
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Giuseppina Bonizzi
- Department of Pathology, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Elisabetta Munzone
- Division of Medical Senology, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Luana Lippolis
- Division of Pathology, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Martina Dameri
- Department of Internal Medicine (DiMI), University of Genoa, Genova, Italy
| | - Francesco Ravera
- Department of Internal Medicine (DiMI), University of Genoa, Genova, Italy
| | - Marco Colleoni
- Division of Medical Senology, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Giuseppe Viale
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Department of Pathology, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Luca Magnani
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Alberto Ballestrero
- IRCCS Ospedale Policlinico San Martino, Genova, Italy
- Department of Internal Medicine (DiMI), University of Genoa, Genova, Italy
| | - Gabriele Zoppoli
- IRCCS Ospedale Policlinico San Martino, Genova, Italy
- Department of Internal Medicine (DiMI), University of Genoa, Genova, Italy
| | - Giancarlo Pruneri
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
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Suba Z. Rosetta Stone for Cancer Cure: Comparison of the Anticancer Capacity of Endogenous Estrogens, Synthetic Estrogens and Antiestrogens. Oncol Rev 2023; 17:10708. [PMID: 37152665 PMCID: PMC10154579 DOI: 10.3389/or.2023.10708] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 03/30/2023] [Indexed: 05/09/2023] Open
Abstract
This work presents the history of the recognition of principal regulatory capacities of estrogen hormones having been mistakenly regarded as breast cancer promoting agents for more than 120 years. Comprehensive analysis of the results of clinical, epidemiological, immunological and molecular studies justified that endogenous estrogens are the principal regulators of embryonic development, survival and reproduction via orchestrating appropriate expression and even edition of all genes in mammalians. Medical use of chemically modified synthetic estrogens caused toxic complications; thromboembolic events and increased cancer risk in female organs as they proved to be endocrine disruptors deregulating estrogen receptors (ERs) rather than their activators. Synthetic estrogen treatment exhibits ambiguous correlations with cancer risk at different sites, which may be attributed to an inhibition of the unliganded activation of estrogen receptors (ERs) coupled with compensatory liganded activation. The principle of estrogen induced breast cancer led to the introduction of antiestrogen therapies against this tumor; inhibition of the liganded activation of estrogen receptors and aromatase enzyme activity. The initial enthusiasm turned into disappointment as the majority of breast cancers proved to be primarily resistant to antiestrogens. In addition, nearly all patients showing earlier good tumor responses to endocrine therapy, later experienced secondary resistance leading to metastatic disease and fatal outcome. Studying the molecular events in tumors responsive and unresponsive to antiestrogen therapy, it was illuminated that a complete inhibition of liganded ER activation stimulates the growth of cancers, while a successful compensatory upregulation of estrogen signal may achieve DNA restoration, tumor regression and patient's survival. Recognition of the principal role of endogenous estrogens in gene expression, gene edition and DNA repair, estrogen treatment and stimulation of ER expression in patients may bring about a great turn in medical practice.
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Wu S, Jiang H, Chen Z, Lu W, Chen Q. Network Pharmacology-Based Study on the Active Ingredients and Mechanism of Pan Ji Sheng Traditional Chinese Medicine Formula in the Treatment of Inflammation. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:5340933. [PMID: 36212968 PMCID: PMC9534616 DOI: 10.1155/2022/5340933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 08/20/2022] [Indexed: 11/17/2022]
Abstract
Background Pan Ji Sheng Formula is a Chinese medicine formula that enables heat-free detoxification as well as anti-inflammatory and immune-boosting properties. This formula contains eight herbs. Its underlying mechanism is unknown. The bioactive ingredients were screened in our work, and the mechanism of this formula was investigated. Methods Using traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP), ingredients in Pan Ji Sheng Chinese medicine formula were screened, and we selected the main bioactive ingredients for web-based research. The targets of bioactive ingredients are primarily obtained from the SwissTargetPrediction and TCMSP databases, and the text mining method is used. STRING and Cytoscape were then used to examine the protein-protein interaction (PPI) networks. To explore the biological function and related pathways, functional annotation and pathway analysis were performed. Results This research discovered 96 bioactive ingredients. Then, 215 potential targets of bioactive ingredients were screened. Through the analysis of the PPI network, we discovered 25 key target genes, which can be described as hub target genes regulated by bioactive ingredients. Bioactive ingredients primarily regulate CASP3, AKT1, JUN, and other proteins. The formula works synergistically to enhance immune response and antiinfection by regulating immune-related pathways, TNF signaling pathways, and apoptosis. Conclusions A variety of bioactive ingredients in the formula could play roles in regulating CASP3, AKT1, and other genes in immune, infection, apoptosis, and tumor-related signaling pathways. Our data point the way forward for future studies on the mechanism of action of this formula.
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Affiliation(s)
- Shiji Wu
- Gaozhou Hospital of Traditional Chinese Medicine, No. 32 Maoming Avenue, Gaozhou 525200, Guangdong, China
| | - Hongliang Jiang
- Gaozhou Hospital of Traditional Chinese Medicine, No. 32 Maoming Avenue, Gaozhou 525200, Guangdong, China
| | - Zongwen Chen
- Gaozhou Hospital of Traditional Chinese Medicine, No. 32 Maoming Avenue, Gaozhou 525200, Guangdong, China
| | - Weining Lu
- Gaozhou Hospital of Traditional Chinese Medicine, No. 32 Maoming Avenue, Gaozhou 525200, Guangdong, China
| | - Qin Chen
- Gaozhou Hospital of Traditional Chinese Medicine, No. 32 Maoming Avenue, Gaozhou 525200, Guangdong, China
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27
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Singer CF, Holst F, Steurer S, Burandt EC, Lax SF, Jakesz R, Rudas M, Stöger H, Greil R, Sauter G, Filipits M, Simon R, Gnant M. Estrogen Receptor Alpha Gene Amplification Is an Independent Predictor of Long-Term Outcome in Postmenopausal Patients with Endocrine-Responsive Early Breast Cancer. Clin Cancer Res 2022; 28:4112-4120. [PMID: 35920686 PMCID: PMC9475247 DOI: 10.1158/1078-0432.ccr-21-4328] [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] [Received: 12/28/2021] [Revised: 03/07/2022] [Accepted: 07/08/2022] [Indexed: 01/07/2023]
Abstract
PURPOSE Estrogen receptor (ER) expression is a prognostic parameter in breast cancer, and a prerequisite for the use of endocrine therapy. In ER+ early breast cancer, however, no receptor-associated biomarker exists that identifies patients with a particularly favorable outcome. We have investigated the value of ESR1 amplification in predicting the long-term clinical outcome in tamoxifen-treated postmenopausal women with endocrine-responsive breast cancer. EXPERIMENTAL DESIGN 394 patients who had been randomized into the tamoxifen-only arm of the prospective randomized ABCSG-06 trial of adjuvant endocrine therapy with available formalin-fixed, paraffin-embedded tumor tissue were included in this analysis. IHC ERα expression was evaluated both locally and in a central lab using the Allred score, while ESR1 gene amplification was evaluated by FISH analysis using the ESR1/CEP6 ratio indicating focal copy number alterations. RESULTS Focal ESR1 copy-number elevations (amplifications) were detected in 187 of 394 (47%) tumor specimens, and were associated with a favorable outcome: After a median follow-up of 10 years, women with intratumoral focal ESR1 amplification had a significantly longer distant recurrence-free survival [adjusted HR, 0.48; 95% confidence interval (CI), 0.26-0.91; P = 0.02] and breast cancer-specific survival (adjusted HR 0.47; 95% CI, 0.27-0.80; P = 0.01) as compared with women without ESR1 amplification. IHC ERα protein expression, evaluated by Allred score, correlated significantly with focal ESR1 amplification (P < 0.0001; χ2 test), but was not prognostic by itself. CONCLUSIONS Focal ESR1 amplification is an independent and powerful predictor for long-term distant recurrence-free and breast cancer-specific survival in postmenopausal women with endocrine-responsive early-stage breast cancer who received tamoxifen for 5 years.
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Affiliation(s)
- Christian F. Singer
- Department of OB/GYN, Medical University of Vienna, Vienna, Austria.,Corresponding Author: Christian F. Singer, Medical University of Vienna, AKH Wien, Waehringer Guertel 18-20, Vienna 1090, Austria. Phone: 4314-0400-28010, Fax: 4314-0400-23230; E-mail:
| | | | - Frederik Holst
- Department of OB/GYN, Medical University of Vienna, Vienna, Austria.,Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Steurer
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eike C. Burandt
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sigurd F. Lax
- Department of Pathology, Medical University of Graz, Graz, Austria.,Hospital Graz II, Graz, Austria.,Johannes Kepler University, School of Medicine, Graz, Austria
| | - Raimund Jakesz
- Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Margaretha Rudas
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Herbert Stöger
- Department of Medicine, Medical University of Graz, Graz, Austria
| | - Richard Greil
- Salzburg Cancer Research Institute - Center for Clinical and Immunology Trials and Cancer Cluster Salzburg; IIIrd Medical Department, Paracelsus Medical University Salzburg, Salzburg, Austria
| | | | - Guido Sauter
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Martin Filipits
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | | | - Ronald Simon
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michael Gnant
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
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Rao S, Han AL, Zukowski A, Kopin E, Sartorius CA, Kabos P, Ramachandran S. Transcription factor-nucleosome dynamics from plasma cfDNA identifies ER-driven states in breast cancer. SCIENCE ADVANCES 2022; 8:eabm4358. [PMID: 36001652 PMCID: PMC9401618 DOI: 10.1126/sciadv.abm4358] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 07/12/2022] [Indexed: 06/09/2023]
Abstract
Genome-wide binding profiles of estrogen receptor (ER) and FOXA1 reflect cancer state in ER+ breast cancer. However, routine profiling of tumor transcription factor (TF) binding is impractical in the clinic. Here, we show that plasma cell-free DNA (cfDNA) contains high-resolution ER and FOXA1 tumor binding profiles for breast cancer. Enrichment of TF footprints in plasma reflects the binding strength of the TF in originating tissue. We defined pure in vivo tumor TF signatures in plasma using ER+ breast cancer xenografts, which can distinguish xenografts with distinct ER states. Furthermore, state-specific ER-binding signatures can partition human breast tumors into groups with significantly different ER expression and mortality. Last, TF footprints in human plasma samples can identify the presence of ER+ breast cancer. Thus, plasma TF footprints enable minimally invasive mapping of the regulatory landscape of breast cancer in humans and open vast possibilities for clinical applications across multiple tumor types.
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Affiliation(s)
- Satyanarayan Rao
- Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USA
- RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO, USA
| | - Amy L. Han
- Department of Medicine/Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Alexis Zukowski
- Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USA
- RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO, USA
| | - Etana Kopin
- Department of Medicine/Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Carol A. Sartorius
- Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Peter Kabos
- RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO, USA
- Department of Medicine/Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO, USA
- University of Colorado Cancer Center, Aurora, CO, USA
| | - Srinivas Ramachandran
- Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USA
- RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO, USA
- University of Colorado Cancer Center, Aurora, CO, USA
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A Novel Attention-Mechanism Based Cox Survival Model by Exploiting Pan-Cancer Empirical Genomic Information. Cells 2022; 11:cells11091421. [PMID: 35563727 PMCID: PMC9100007 DOI: 10.3390/cells11091421] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/15/2022] [Accepted: 04/19/2022] [Indexed: 01/27/2023] Open
Abstract
Cancer prognosis is an essential goal for early diagnosis, biomarker selection, and medical therapy. In the past decade, deep learning has successfully solved a variety of biomedical problems. However, due to the high dimensional limitation of human cancer transcriptome data and the small number of training samples, there is still no mature deep learning-based survival analysis model that can completely solve problems in the training process like overfitting and accurate prognosis. Given these problems, we introduced a novel framework called SAVAE-Cox for survival analysis of high-dimensional transcriptome data. This model adopts a novel attention mechanism and takes full advantage of the adversarial transfer learning strategy. We trained the model on 16 types of TCGA cancer RNA-seq data sets. Experiments show that our module outperformed state-of-the-art survival analysis models such as the Cox proportional hazard model (Cox-ph), Cox-lasso, Cox-ridge, Cox-nnet, and VAECox on the concordance index. In addition, we carry out some feature analysis experiments. Based on the experimental results, we concluded that our model is helpful for revealing cancer-related genes and biological functions.
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Efficient prediction of a spatial transcriptomics profile better characterizes breast cancer tissue sections without costly experimentation. Sci Rep 2022; 12:4133. [PMID: 35260632 PMCID: PMC8904587 DOI: 10.1038/s41598-022-07685-4] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 02/21/2022] [Indexed: 02/07/2023] Open
Abstract
Spatial transcriptomics is an emerging technology requiring costly reagents and considerable skills, limiting the identification of transcriptional markers related to histology. Here, we show that predicted spatial gene-expression in unmeasured regions and tissues can enhance biologists’ histological interpretations. We developed the Deep learning model for Spatial gene Clusters and Expression, DeepSpaCE, and confirmed its performance using the spatial-transcriptome profiles and immunohistochemistry images of consecutive human breast cancer tissue sections. For example, the predicted expression patterns of SPARC, an invasion marker, highlighted a small tumor-invasion region difficult to identify using raw spatial transcriptome data alone because of a lack of measurements. We further developed semi-supervised DeepSpaCE using unlabeled histology images and increased the imputation accuracy of consecutive sections, enhancing applicability for a small sample size. Our method enables users to derive hidden histological characters via spatial transcriptome and gene annotations, leading to accelerated biological discoveries without additional experiments.
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31
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Scheidmann MC, Castro-Giner F, Strittmatter K, Krol I, Paasinen-Sohns A, Scherrer R, Donato C, Gkountela S, Szczerba BM, Diamantopoulou Z, Muenst S, Vlajnic T, Kunz L, Vetter M, Rochlitz C, Taylor V, Giachino C, Schroeder T, Platt RJ, Aceto N. An In Vivo CRISPR Screen Identifies Stepwise Genetic Dependencies of Metastatic Progression. Cancer Res 2022; 82:681-694. [PMID: 34916221 PMCID: PMC7612409 DOI: 10.1158/0008-5472.can-21-3908] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 11/30/2021] [Accepted: 12/13/2021] [Indexed: 11/16/2022]
Abstract
Blood-borne metastasis of breast cancer involves a series of tightly regulated sequential steps, including the growth of a primary tumor lesion, intravasation of circulating tumor cells (CTC), and adaptation in various distant metastatic sites. The genes orchestrating each of these steps are poorly understood in physiologically relevant contexts, owing to the rarity of experimental models that faithfully recapitulate the biology, growth kinetics, and tropism of human breast cancer. Here, we conducted an in vivo loss-of-function CRISPR screen in newly derived CTC xenografts, unique in their ability to spontaneously mirror the human disease, and identified specific genetic dependencies for each step of the metastatic process. Validation experiments revealed sensitivities to inhibitors that are already available, such as PLK1 inhibitors, to prevent CTC intravasation. Together, these findings present a new tool to reclassify driver genes involved in the spread of human cancer, providing insights into the biology of metastasis and paving the way to test targeted treatment approaches. SIGNIFICANCE A loss-of-function CRISPR screen in human CTC-derived xenografts identifies genes critical for individual steps of the metastatic cascade, suggesting novel drivers and treatment opportunities for metastatic breast cancers.
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MESH Headings
- Animals
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Breast Neoplasms/blood
- Breast Neoplasms/genetics
- Breast Neoplasms/pathology
- CRISPR-Cas Systems
- Cell Cycle Proteins/genetics
- Cell Cycle Proteins/metabolism
- Cell Line, Tumor
- Clustered Regularly Interspaced Short Palindromic Repeats/genetics
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Mice, Inbred NOD
- Mice, Knockout
- Mice, SCID
- Neoplasm Metastasis
- Neoplastic Cells, Circulating/metabolism
- Neoplastic Cells, Circulating/pathology
- Protein Serine-Threonine Kinases/genetics
- Protein Serine-Threonine Kinases/metabolism
- Proto-Oncogene Proteins/genetics
- Proto-Oncogene Proteins/metabolism
- RNA, Guide, CRISPR-Cas Systems/genetics
- RNA, Guide, CRISPR-Cas Systems/metabolism
- RNA-Seq/methods
- Survival Analysis
- Xenograft Model Antitumor Assays/methods
- Polo-Like Kinase 1
- Mice
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Affiliation(s)
- Manuel C. Scheidmann
- Department of Biomedicine, Cancer Metastasis Laboratory, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Francesc Castro-Giner
- Department of Biomedicine, Cancer Metastasis Laboratory, University of Basel and University Hospital Basel, Basel, Switzerland
- Department of Biology, Molecular Oncology Laboratory, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Karin Strittmatter
- Department of Biomedicine, Cancer Metastasis Laboratory, University of Basel and University Hospital Basel, Basel, Switzerland
- Department of Biology, Molecular Oncology Laboratory, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
| | - Ilona Krol
- Department of Biomedicine, Cancer Metastasis Laboratory, University of Basel and University Hospital Basel, Basel, Switzerland
- Department of Biology, Molecular Oncology Laboratory, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
| | - Aino Paasinen-Sohns
- Department of Biomedicine, Cancer Metastasis Laboratory, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Ramona Scherrer
- Department of Biomedicine, Cancer Metastasis Laboratory, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Cinzia Donato
- Department of Biomedicine, Cancer Metastasis Laboratory, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Sofia Gkountela
- Department of Biomedicine, Cancer Metastasis Laboratory, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Barbara M. Szczerba
- Department of Biomedicine, Cancer Metastasis Laboratory, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Zoi Diamantopoulou
- Department of Biomedicine, Cancer Metastasis Laboratory, University of Basel and University Hospital Basel, Basel, Switzerland
- Department of Biology, Molecular Oncology Laboratory, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
| | - Simone Muenst
- Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Tatjana Vlajnic
- Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Leo Kunz
- Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland
| | - Marcus Vetter
- Department of Medical Oncology, University Hospital Basel, Basel, Switzerland
| | - Christoph Rochlitz
- Department of Medical Oncology, University Hospital Basel, Basel, Switzerland
| | - Verdon Taylor
- Department of Biomedicine, Embryology and Stem Cell Biology Laboratory, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Claudio Giachino
- Department of Biomedicine, Embryology and Stem Cell Biology Laboratory, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Timm Schroeder
- Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland
| | - Randall J. Platt
- Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland
| | - Nicola Aceto
- Department of Biomedicine, Cancer Metastasis Laboratory, University of Basel and University Hospital Basel, Basel, Switzerland
- Department of Biology, Molecular Oncology Laboratory, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
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32
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Shevkar C, Armarkar A, Weerasinghe R, Maduranga K, Pandey K, Behera SK, Kalia K, Paranagama P, Kate AS. Cytotoxic Bioxanthracene and Macrocyclic Polyester from Endolichenic Fungus Talaromyces pinophilus: In-Vitro and In-Silico Analysis. Indian J Microbiol 2022; 62:204-214. [DOI: 10.1007/s12088-021-00994-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 12/03/2021] [Indexed: 11/30/2022] Open
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33
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Sekar S, Subbamanda Y, Pullaguri N, Sharma A, Sahu C, Kumar R, Bhargava A. Isoform-specific expression of T-type voltage-gated calcium channels and estrogen receptors in breast cancer reveals specific isoforms that may be potential targets. CURRENT RESEARCH IN BIOTECHNOLOGY 2022. [DOI: 10.1016/j.crbiot.2022.09.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022] Open
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34
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Kumar S, Gupta S, Maurya AP, Singh R, Nigam S. Hormonal and Targeted Treatments in Breast Cancer. Breast Cancer 2022. [DOI: 10.1007/978-981-16-4546-4_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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35
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Fatema K, Luelling S, Kirkham M, Pavek A, Heyneman AL, Barrott J. Epigenetics and precision medicine in bone and soft tissue sarcomas. EPIGENETICS IN PRECISION MEDICINE 2022:147-191. [DOI: 10.1016/b978-0-12-823008-4.00009-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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36
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Patel JM, Jeselsohn RM. Estrogen Receptor Alpha and ESR1 Mutations in Breast Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1390:171-194. [DOI: 10.1007/978-3-031-11836-4_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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37
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Porras L, Ismail H, Mader S. Positive Regulation of Estrogen Receptor Alpha in Breast Tumorigenesis. Cells 2021; 10:cells10112966. [PMID: 34831189 PMCID: PMC8616513 DOI: 10.3390/cells10112966] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/23/2021] [Accepted: 10/24/2021] [Indexed: 12/31/2022] Open
Abstract
Estrogen receptor alpha (ERα, NR3A1) contributes through its expression in different tissues to a spectrum of physiological processes, including reproductive system development and physiology, bone mass maintenance, as well as cardiovascular and central nervous system functions. It is also one of the main drivers of tumorigenesis in breast and uterine cancer and can be targeted by several types of hormonal therapies. ERα is expressed in a subset of luminal cells corresponding to less than 10% of normal mammary epithelial cells and in over 70% of breast tumors (ER+ tumors), but the basis for its selective expression in normal or cancer tissues remains incompletely understood. The mapping of alternative promoters and regulatory elements has delineated the complex genomic structure of the ESR1 gene and shed light on the mechanistic basis for the tissue-specific regulation of ESR1 expression. However, much remains to be uncovered to better understand how ESR1 expression is regulated in breast cancer. This review recapitulates the current body of knowledge on the structure of the ESR1 gene and the complex mechanisms controlling its expression in breast tumors. In particular, we discuss the impact of genetic alterations, chromatin modifications, and enhanced expression of other luminal transcription regulators on ESR1 expression in tumor cells.
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38
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Lyu R, Zhu X, Shen Y, Xiong L, Liu L, Liu H, Wu F, Argueta C, Tan L. Tumour suppressor TET2 safeguards enhancers from aberrant DNA methylation and epigenetic reprogramming in ERα-positive breast cancer cells. Epigenetics 2021; 17:1180-1194. [PMID: 34689714 DOI: 10.1080/15592294.2021.1997405] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
Aberrant DNA methylation is an epigenetic hallmark of malignant tumours. The DNA methylation level is regulated by not only DNA methyltransferases (DNMTs) but also Ten-Eleven Translocation (TET) family proteins. However, the exact role of TET genes in breast cancer remains controversial. Here, we uncover that the ERα-positive breast cancer patients with high TET2 mRNA expression had better overall survival rates. Consistently, knockout of TET2 promotes the tumorigenesis of ERα-positive MCF7 breast cancer cells. Mechanistically, TET2 loss leads to aberrant DNA methylation (gain of 5mC) at a large proportion of enhancers, accompanied by significant reduction in H3K4me1 and H3K27ac enrichment. By analysing the epigenetically reprogrammed enhancers, we identify oestrogen responsive element (ERE) as one of the enriched motifs of transcriptional factors. Importantly, TET2 loss impairs 17beta-oestradiol (E2)-induced transcription of the epigenetically reprogrammed EREs-associated genes through attenuating the binding of ERα. Taken together, these findings shed light on our understanding of the epigenetic mechanisms underlying the enhancer reprogramming during breast cancer pathogenesis.
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Affiliation(s)
- Ruitu Lyu
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Xuguo Zhu
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yinghui Shen
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Lijun Xiong
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Lu Liu
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Hang Liu
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Feizhen Wu
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Christian Argueta
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Li Tan
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
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39
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Khandker SS, Shakil MS, Hossen MS. Gold Nanoparticles; Potential Nanotheranostic Agent in Breast Cancer: A Comprehensive Review with Systematic Search Strategy. Curr Drug Metab 2021; 21:579-598. [PMID: 32520684 DOI: 10.2174/1389200221666200610173724] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 03/19/2020] [Accepted: 04/02/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Breast cancer is a heterogeneous disease typically prevalent among women and is the second-largest cause of death worldwide. Early diagnosis is the key to minimize the cancer-induced complication, however, the conventional diagnostic strategies have been sluggish, complex, and, to some extent, non-specific. Therapeutic tools are not so convenient and side effects of current therapies offer the development of novel theranostic tool to combat this deadly disease. OBJECTIVE This article aims to summarize the advances in the diagnosis and treatment of breast cancer with gold nanoparticles (GNP or AuNP). METHODS A systematic search was conducted in the three popular electronic online databases including PubMed, Google Scholar, and Web of Science, regarding GNP as breast cancer theranostics. RESULTS Published literature demonstrated that GNPs tuned with photosensitive moieties, nanomaterials, drugs, peptides, nucleotide, peptides, antibodies, aptamer, and other biomolecules improve the conventional diagnostic and therapeutic strategies of breast cancer management with minimum cytotoxic effect. GNP derived diagnosis system assures reproducibility, reliability, and accuracy cost-effectively. Additionally, surface-modified GNP displayed theranostic potential even in the metastatic stage of breast cancer. CONCLUSION Divergent strategies have shown the theranostic potential of surface tuned GNPs against breast cancer even in the metastatic stage with minimum cytotoxic effects both in vitro and in vivo.
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Affiliation(s)
- Shahad Saif Khandker
- Department of Biochemistry and Molecular Biology, Jahangirnagar University, Savar, Dhaka, Bangladesh
| | - Md Salman Shakil
- Department of Pharmacology & Toxicology, University of Otago, 362 Leith St., North Dunedin, Dunedin 9016, New Zealand
| | - Md Sakib Hossen
- Department of Biochemistry, Primeasia University, Banani, Dhaka, Bangladesh
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40
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Yu KD, Cai YW, Wu SY, Shui RH, Shao ZM. Estrogen receptor-low breast cancer: Biology chaos and treatment paradox. Cancer Commun (Lond) 2021; 41:968-980. [PMID: 34251757 PMCID: PMC8504145 DOI: 10.1002/cac2.12191] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 04/23/2021] [Accepted: 06/19/2021] [Indexed: 02/03/2023] Open
Abstract
Hormone receptor testing mainly serves the purpose of guiding treatment choices for breast cancer patients. Patients with estrogen receptor (ER)‐positive breast cancers show significant response to endocrine therapy. However, the methods to define ER status and eligibility for treatment remain controversial. Despite recent guidelines considering staining ≥1% of tumor nuclei by immunohistology as ER‐positive, it has raised concerns on the benefit of endocrine therapy for tumors with ER 1%‐10% expression, termed “ER‐low positive”. This subgroup accounts for 3% to 9% of all patients and is likely to have unique molecular features, and therefore distinct therapeutic response to endocrine therapy compared with ER‐high positive tumors. The latest guidelines did not provide detailed descriptions for those patients, resulting in inconsistent treatment strategies. Consequently, we aimed to resolve this dilemma comprehensively. This review discusses molecular traits and recent ER‐low positive breast cancer innovations, highlighting molecular‐targeted treatment rather than traditional unified endocrine therapy for future basic and clinical research.
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Affiliation(s)
- Ke-Da Yu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, P. R. China.,Shanghai Medical College, Fudan University, Shanghai, 200032, P. R. China
| | - Yu-Wen Cai
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, P. R. China.,Shanghai Medical College, Fudan University, Shanghai, 200032, P. R. China
| | - Song-Yang Wu
- Shanghai Medical College, Fudan University, Shanghai, 200032, P. R. China
| | - Ruo-Hong Shui
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, P. R. China
| | - Zhi-Ming Shao
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, P. R. China.,Shanghai Key Laboratory of Breast Cancer, Shanghai, 200032, P. R. China
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41
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Farnoosh G, Saeedi-Boroujeni A, Jalali A, Keikhaei B, Mahmoudian-Sani MR. Polymorphisms in genes involved in breast cancer among Iranian patients. Per Med 2021; 18:153-169. [PMID: 33565318 DOI: 10.2217/pme-2020-0003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
This review gives a summary of the important genetic polymorphisms in breast cancer with a focus on people in Iran. Several single nucleotide polymorphisms were considered as breast cancer susceptibility polymorphisms within genes (STK15, ERRs, ESR1, p53, SEP15, AURKA, SHBG, SRC, FAS, VEGF, XRCC1, GST, NFκB1, XPC, XRCC3, sirtuin-3, NKG2D). Cytosine-adenine repeat (IGF-I), rs3877899, G-2548A, GGC (eRF3a/GSPT1), IVS2nt-124A/G have shown an increased risk of breast cancers and a decreased risk has been observed in 4G/5G (PAI-1), rs6505162, tri-nucleotide (GCG TGFBR1). We observed that the signaling pathways and antioxidant related genes are the main molecular processes associated with breast cancer progression. Further studies on types of polymorphisms in breast cancer could validate the prognostic value of biomarkers.
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Affiliation(s)
- Gholamreza Farnoosh
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Ali Saeedi-Boroujeni
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Immunology Today, Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Akram Jalali
- Department of Molecular Medicine & Genetics, School of Medicine Hamadan University of Medical Sciences
| | - Bijan Keikhaei
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammad-Reza Mahmoudian-Sani
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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42
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Emad A, Sinha S. Inference of phenotype-relevant transcriptional regulatory networks elucidates cancer type-specific regulatory mechanisms in a pan-cancer study. NPJ Syst Biol Appl 2021; 7:9. [PMID: 33558504 PMCID: PMC7870953 DOI: 10.1038/s41540-021-00169-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Accepted: 01/05/2021] [Indexed: 01/30/2023] Open
Abstract
Reconstruction of transcriptional regulatory networks (TRNs) is a powerful approach to unravel the gene expression programs involved in healthy and disease states of a cell. However, these networks are usually reconstructed independent of the phenotypic (or clinical) properties of the samples. Therefore, they may confound regulatory mechanisms that are specifically related to a phenotypic property with more general mechanisms underlying the full complement of the analyzed samples. In this study, we develop a method called InPheRNo to identify "phenotype-relevant" TRNs. This method is based on a probabilistic graphical model that models the simultaneous effects of multiple transcription factors (TFs) on their target genes and the statistical relationship between the target genes' expression and the phenotype. Extensive comparison of InPheRNo with related approaches using primary tumor samples of 18 cancer types from The Cancer Genome Atlas reveals that InPheRNo can accurately reconstruct cancer type-relevant TRNs and identify cancer driver TFs. In addition, survival analysis reveals that the activity level of TFs with many target genes could distinguish patients with poor prognosis from those with better prognosis.
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Affiliation(s)
- Amin Emad
- Department of Electrical and Computer Engineering, McGill University, Montreal, QC, Canada.
| | - Saurabh Sinha
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
- Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
- Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
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43
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Hou J, Ye X, Wang Y, Li C. Stratification of Estrogen Receptor-Negative Breast Cancer Patients by Integrating the Somatic Mutations and Transcriptomic Data. Front Genet 2021; 12:610087. [PMID: 33613637 PMCID: PMC7886807 DOI: 10.3389/fgene.2021.610087] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 01/04/2021] [Indexed: 01/26/2023] Open
Abstract
Patients with estrogen receptor-negative breast cancer generally have a worse prognosis than estrogen receptor-positive patients. Nevertheless, a significant proportion of the estrogen receptor-negative cases have favorable outcomes. Identifying patients with a good prognosis, however, remains difficult, as recent studies are quite limited. The identification of molecular biomarkers is needed to better stratify patients. The significantly mutated genes may be potentially used as biomarkers to identify the subtype and to predict outcomes. To identify the biomarkers of receptor-negative breast cancer among the significantly mutated genes, we developed a workflow to screen significantly mutated genes associated with the estrogen receptor in breast cancer by a gene coexpression module. The similarity matrix was calculated with distance correlation to obtain gene modules through a weighted gene coexpression network analysis. The modules highly associated with the estrogen receptor, called important modules, were enriched for breast cancer-related pathways or disease. To screen significantly mutated genes, a new gene list was obtained through the overlap of the important module genes and the significantly mutated genes. The genes on this list can be used as biomarkers to predict survival of estrogen receptor-negative breast cancer patients. Furthermore, we selected six hub significantly mutated genes in the gene list which were also able to separate these patients. Our method provides a new and alternative method for integrating somatic gene mutations and expression data for patient stratification of estrogen receptor-negative breast cancers.
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Affiliation(s)
| | - Xiufen Ye
- College of Intelligent Systems Science and Engineering, Harbin Engineering University, Harbin, China
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44
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Blatt EB, Kopplin N, Kumar S, Mu P, Conzen SD, Raj GV. Overcoming oncogene addiction in breast and prostate cancers: a comparative mechanistic overview. Endocr Relat Cancer 2021; 28:R31-R46. [PMID: 33263560 PMCID: PMC8218927 DOI: 10.1530/erc-20-0272] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 11/23/2020] [Indexed: 02/06/2023]
Abstract
Prostate cancer (PCa) and breast cancer (BCa) are both hormone-dependent cancers that require the androgen receptor (AR) and estrogen receptor (ER, ESR1) for growth and proliferation, respectively. Endocrine therapies that target these nuclear receptors (NRs) provide significant clinical benefit for metastatic patients. However, these therapeutic strategies are seldom curative and therapy resistance is prevalent. Because the vast majority of therapy-resistant PCa and BCa remain dependent on the augmented activity of their primary NR driver, common mechanisms of resistance involve enhanced NR signaling through overexpression, mutation, or alternative splicing of the receptor, coregulator alterations, and increased intracrine hormonal synthesis. In addition, a significant subset of endocrine therapy-resistant tumors become independent of their primary NR and switch to alternative NR or transcriptional drivers. While these hormone-dependent cancers generally employ similar mechanisms of endocrine therapy resistance, distinct differences between the two tumor types have been observed. In this review, we compare and contrast the most frequent mechanisms of antiandrogen and antiestrogen resistance, and provide potential therapeutic strategies for targeting both advanced PCa and BCa.
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Affiliation(s)
- Eliot B Blatt
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Noa Kopplin
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Shourya Kumar
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Ping Mu
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Suzanne D Conzen
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Ganesh V Raj
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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45
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Yuyama M, Misawa T, Demizu Y, Kanaya T, Kurihara M. Design and synthesis of novel estrogen receptor antagonists with acetal containing biphenylmethane skeleton. RESULTS IN CHEMISTRY 2021. [DOI: 10.1016/j.rechem.2021.100124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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Font-Díaz J, Jiménez-Panizo A, Caelles C, Vivanco MDM, Pérez P, Aranda A, Estébanez-Perpiñá E, Castrillo A, Ricote M, Valledor AF. Nuclear receptors: Lipid and hormone sensors with essential roles in the control of cancer development. Semin Cancer Biol 2020; 73:58-75. [PMID: 33309851 DOI: 10.1016/j.semcancer.2020.12.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 12/04/2020] [Accepted: 12/04/2020] [Indexed: 12/15/2022]
Abstract
Nuclear receptors (NRs) are a superfamily of ligand-activated transcription factors that act as biological sensors and use a combination of mechanisms to modulate positively and negatively gene expression in a spatial and temporal manner. The highly orchestrated biological actions of several NRs influence the proliferation, differentiation, and apoptosis of many different cell types. Synthetic ligands for several NRs have been the focus of extensive drug discovery efforts for cancer intervention. This review summarizes the roles in tumour growth and metastasis of several relevant NR family members, namely androgen receptor (AR), estrogen receptor (ER), glucocorticoid receptor (GR), thyroid hormone receptor (TR), retinoic acid receptors (RARs), retinoid X receptors (RXRs), peroxisome proliferator-activated receptors (PPARs), and liver X receptors (LXRs). These studies are key to develop improved therapeutic agents based on novel modes of action with reduced side effects and overcoming resistance.
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Affiliation(s)
- Joan Font-Díaz
- Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Barcelona, 08028, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, 08028, Spain
| | - Alba Jiménez-Panizo
- Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, 08028, Spain; Department of Biochemistry and Molecular Biomedicine, School of Biology, University of Barcelona, Barcelona, 08028, Spain
| | - Carme Caelles
- Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, 08028, Spain; Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, University of Barcelona, Barcelona, 08028, Spain
| | - María dM Vivanco
- CIC bioGUNE, Basque Research Technology Alliance, BRTA, Bizkaia Technology Park, Derio, 48160, Spain
| | - Paloma Pérez
- Instituto de Biomedicina de Valencia (IBV)-CSIC, Valencia, 46010, Spain
| | - Ana Aranda
- Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Madrid, 28029, Spain
| | - Eva Estébanez-Perpiñá
- Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, 08028, Spain; Department of Biochemistry and Molecular Biomedicine, School of Biology, University of Barcelona, Barcelona, 08028, Spain
| | - Antonio Castrillo
- Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Madrid, 28029, Spain; Unidad de Biomedicina, (Unidad Asociada al CSIC), Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Universidad de Las Palmas, Gran Canaria, 35001, Spain
| | - Mercedes Ricote
- Area of Myocardial Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, 28029, Spain
| | - Annabel F Valledor
- Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Barcelona, 08028, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, 08028, Spain.
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Lee N, Park MJ, Song W, Jeon K, Jeong S. Currently Applied Molecular Assays for Identifying ESR1 Mutations in Patients with Advanced Breast Cancer. Int J Mol Sci 2020; 21:ijms21228807. [PMID: 33233830 PMCID: PMC7699999 DOI: 10.3390/ijms21228807] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 11/17/2020] [Accepted: 11/19/2020] [Indexed: 12/11/2022] Open
Abstract
Approximately 70% of breast cancers, the leading cause of cancer-related mortality worldwide, are positive for the estrogen receptor (ER). Treatment of patients with luminal subtypes is mainly based on endocrine therapy. However, ER positivity is reduced and ESR1 mutations play an important role in resistance to endocrine therapy, leading to advanced breast cancer. Various methodologies for the detection of ESR1 mutations have been developed, and the most commonly used method is next-generation sequencing (NGS)-based assays (50.0%) followed by droplet digital PCR (ddPCR) (45.5%). Regarding the sample type, tissue (50.0%) was more frequently used than plasma (27.3%). However, plasma (46.2%) became the most used method in 2016-2019, in contrast to 2012-2015 (22.2%). In 2016-2019, ddPCR (61.5%), rather than NGS (30.8%), became a more popular method than it was in 2012-2015. The easy accessibility, non-invasiveness, and demonstrated usefulness with high sensitivity of ddPCR using plasma have changed the trends. When using these assays, there should be a comprehensive understanding of the principles, advantages, vulnerability, and precautions for interpretation. In the future, advanced NGS platforms and modified ddPCR will benefit patients by facilitating treatment decisions efficiently based on information regarding ESR1 mutations.
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Affiliation(s)
- Nuri Lee
- Department of Laboratory Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07440, Korea; (N.L.); (M.-J.P.); (W.S.)
| | - Min-Jeong Park
- Department of Laboratory Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07440, Korea; (N.L.); (M.-J.P.); (W.S.)
| | - Wonkeun Song
- Department of Laboratory Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07440, Korea; (N.L.); (M.-J.P.); (W.S.)
| | - Kibum Jeon
- Department of Laboratory Medicine, Hangang Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07440, Korea;
| | - Seri Jeong
- Department of Laboratory Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07440, Korea; (N.L.); (M.-J.P.); (W.S.)
- Correspondence: ; Tel.: +82-845-5305
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ESR1 genetic alterations and their association with clinicopathologic characteristics in advanced breast cancer: a single academic institution experience. Hum Pathol 2020; 107:80-86. [PMID: 33157125 DOI: 10.1016/j.humpath.2020.10.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 10/27/2020] [Accepted: 10/30/2020] [Indexed: 11/21/2022]
Abstract
Estrogen receptor (ER) alpha, a ligand-dependent nuclear transcription factor encoded by the ESR1 gene, is expressed in 70% of breast carcinomas (BCs) and is used as a target for endocrine-based therapies. However, some patients develop resistance to endocrine-based therapies due to ESR1 mutation, which leads to constitutive activation in the absence of ligand. We retrospectively analyzed 223 clinically advanced BCs using the FoundationOne CDX assay and found 13.9% (31/223) of cases had ESR1 genetic alterations (26 mutations and 5 amplifications). All ESR1 mutations occurred within the ligand binding domain, with the most prevalent being Y537S (42.3%) and D538G (38.5%), and all ESR1-mutated cases had a history of aromatase inhibitor use. No significant difference in clinicopathologic features was identified between ESR1-mutated and ESR1-amplified cases except higher frequency of HER2 positivity and TP53 mutations in ESR1-amplified cases. The prevalence of ESR1 mutations in ER-positive BCs was 19.1% (26/136). In comparison to ESR1-nonmutated ER-positive cases, ESR1-mutated cases demonstrated significantly higher percentage of tumor cells with ER and progesterone receptor expression, an increased tendency for overall distant metastasis and liver metastasis, higher frequency of FGF3/4/19 mutations, lower frequency of TP53 mutation, but no difference in overall survival and metastatic/recurrent intervals. In conclusion, our findings suggest that development of ESR1 mutations are selected for under the influence of estrogen deprivation, and a positive correlation between ESR1 mutations and ER protein expression may exist.
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Jin J, Wu Y, Chen J, Shen Y, Zhang L, Zhang H, Chen L, Yuan H, Chen H, Zhang W, Luan X. The peptide PROTAC modality: a novel strategy for targeted protein ubiquitination. Theranostics 2020; 10:10141-10153. [PMID: 32929339 PMCID: PMC7481416 DOI: 10.7150/thno.46985] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 07/30/2020] [Indexed: 02/07/2023] Open
Abstract
Despite dramatic advances in drug discovery over the decades, effective therapeutic strategies for cancers treatment are still in urgent demands. PROteolysis TArgeting Chimera (PROTAC), a novel therapeutic modality, has been vigorously promoted in preclinical and clinical applications. Unlike small molecule PROTAC, peptide PROTAC (p-PROTAC) with advantages of high specificity and low toxicity, while avoiding the limitations of shallow binding pockets through large interacting surfaces, provides promising substitutions for E3 ubiquitin ligase complex-mediated ubiquitination of "undruggable proteins". It is worth noting that successful applications of p-PROTAC still have some obstacles, including low stability and poor membrane permeability. Hence, we highlight that p-PROTAC combined with cell-penetrating peptides, constrained conformation technique, and targeted delivery systems could be the future efforts for potential translational research.
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Affiliation(s)
- Jinmei Jin
- Institute of Interdisciplinary Integrative Medicine Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ye Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jinjiao Chen
- Institute of Interdisciplinary Integrative Medicine Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Yiwen Shen
- Institute of Interdisciplinary Integrative Medicine Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Lijun Zhang
- Institute of Interdisciplinary Integrative Medicine Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hong Zhang
- Institute of Interdisciplinary Integrative Medicine Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Lili Chen
- Institute of Interdisciplinary Integrative Medicine Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hebao Yuan
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109 US
| | - Hongzhuan Chen
- Institute of Interdisciplinary Integrative Medicine Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Department of Pharmacology and Chemical Biology, Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Weidong Zhang
- Institute of Interdisciplinary Integrative Medicine Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xin Luan
- Institute of Interdisciplinary Integrative Medicine Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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Yokoo H, Ohoka N, Naito M, Demizu Y. Design and synthesis of peptide-based chimeric molecules to induce degradation of the estrogen and androgen receptors. Bioorg Med Chem 2020; 28:115595. [PMID: 32631565 DOI: 10.1016/j.bmc.2020.115595] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 06/05/2020] [Accepted: 06/08/2020] [Indexed: 01/12/2023]
Abstract
Peptide-based inducers of estrogen receptor (ER) α and androgen receptor (AR) degradations via the ubiquitin-proteasome system (UPS) were developed. The designated inducers were composed of two biologically active scaffolds: the helical peptide PERM3, which is an LXXLL-like mimic of the coactivator SRC-1, and various small molecules (MV1, LCL161, VH032, and POM) that bind to E3 ligases (IAPs, VHL, and cereblon, respectively), to induce ubiquitylation of nuclear receptors that bind to SRC-1. All of the synthesized chimeric E3 ligand-containing molecules induced the UPS-mediated degradation of ERα and AR. The PERM3 peptide was applicable for the development of the ERα and AR degraders using these E3 ligands.
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Affiliation(s)
- Hidetomo Yokoo
- National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan; Graduate School of Medical Health Sciences, Yokohama City University, Yokohama, Kanagawa 230-0045, Japan
| | - Nobumichi Ohoka
- National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan
| | - Mikihiko Naito
- National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan
| | - Yosuke Demizu
- National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan; Graduate School of Medical Health Sciences, Yokohama City University, Yokohama, Kanagawa 230-0045, Japan.
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