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Atallah NM, Makhlouf S, Nabil M, Ibrahim A, Toss MS, Mongan NP, Rakha E. Characterisation of HER2-Driven Morphometric Signature in Breast Cancer and Prediction of Risk of Recurrence. Cancer Med 2025; 14:e70852. [PMID: 40243160 PMCID: PMC12004275 DOI: 10.1002/cam4.70852] [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: 09/24/2024] [Revised: 03/17/2025] [Accepted: 03/26/2025] [Indexed: 04/18/2025] Open
Abstract
INTRODUCTION Human epidermal growth factor receptor 2-positive (HER2-positive) breast cancer (BC) is a heterogeneous disease. In this study, we hypothesised that the degree of HER2 oncogenic activity, and hence response to anti-HER2 therapy is translated into a morphological signature that can be of prognostic/predictive value. METHODS We developed a HER2-driven signature based on a set of morphometric features identified through digital image analysis and visual assessment in a sizable cohort of BC patients. HER2-enriched molecular sub-type (HER2-E) was used for validation, and pathway enrichment analysis was performed to assess HER2 pathway activity in the signature-positive cases. The predictive utility of this signature was evaluated in post-adjuvant HER2-positive BC patients. RESULTS A total of 57 morphometric features were evaluated; of them, 22 features were significantly associated with HER2 positivity. HER2 IHC score 3+/oestrogen receptor-negative tumours were significantly associated with HER2-related morphometric features compared to other HER2 classes including HER2 IHC 2+ with gene amplification, and they showed the least intra-tumour morphological heterogeneity. Tumours displaying HER2-driven morphometric signature showed the strongest association with PAM50 HER2-E sub-type and were enriched with ERBB signalling pathway compared to signature-negative cases. BC patients with positive HER2 morphometric signature showed prolonged distant metastasis-free survival post-adjuvant anti-HER2 therapy (p = 0.007). The clinico-morphometric prognostic index demonstrated an 87% accuracy in predicting recurrence risk. CONCLUSION Our findings underscore the strong prognostic and predictive correlation between HER2 histo-morphometric features and response to targeted anti-HER2 therapy.
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Affiliation(s)
- N. M. Atallah
- Translational Medical Science, School of MedicineThe University of Nottingham and Nottingham University Hospitals NHS TrustNottinghamUK
- Department of Pathology, Faculty of MedicineMenoufia UniversityShebin El‐KomEgypt
| | - S. Makhlouf
- Translational Medical Science, School of MedicineThe University of Nottingham and Nottingham University Hospitals NHS TrustNottinghamUK
- Department of Pathology, Faculty of MedicineAssiut UniversityAssuitEgypt
| | - M. Nabil
- Department of Computer Science, Faculty of MedicineMenoufia UniversityShebin El‐KomEgypt
| | - A. Ibrahim
- Translational Medical Science, School of MedicineThe University of Nottingham and Nottingham University Hospitals NHS TrustNottinghamUK
- Department of PathologySuez Canal UniversityIsmailiaEgypt
| | - M. S. Toss
- Translational Medical Science, School of MedicineThe University of Nottingham and Nottingham University Hospitals NHS TrustNottinghamUK
- Histopathology DepartmentRoyal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation TrustSheffieldUK
| | - N. P. Mongan
- School of Veterinary Medicine and SciencesUniversity of NottinghamSutton BoningtonUK
- Department of PharmacologyWeill Cornell MedicineNew YorkNew YorkUSA
| | - E. Rakha
- Translational Medical Science, School of MedicineThe University of Nottingham and Nottingham University Hospitals NHS TrustNottinghamUK
- Department of Pathology, Faculty of MedicineMenoufia UniversityShebin El‐KomEgypt
- Pathology DepartmentHamad Medical CorporationDohaQatar
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Noyan S, Dedeoğlu BG. Upregulation of miR-99b-5p Modulates ESR1 Expression as an Adaptive Mechanism to Circumvent Drug Response via Facilitating ER/HER2 Crosstalk. Balkan Med J 2025; 42:150-156. [PMID: 40033677 PMCID: PMC11881538 DOI: 10.4274/balkanmedj.galenos.2025.2024-12-47] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 02/17/2025] [Indexed: 03/05/2025] Open
Abstract
Background Endocrine resistance remains a significant therapeutic challenge in estrogen receptor-positive (ER+) breast cancer, the most common subtype, contributing to increased morbidity and mortality. The interaction between ER and HER family receptors, particularly HER2 and epidermal growth factor receptor (EGFR), drives resistance to standard therapies such as tamoxifen and trastuzumab by activating key signaling pathways, including PI3K/AKT and RAS/MAPK. Dysregulated miRNAs, which are non-coding gene expression regulators, have been linked to therapy response. Aims To investigate the role of miR-99b-5p in ER-HER2/EGFR crosstalk in BT-474 cells. Study Design Experimental study. Methods The expression profile and prognostic significance of miR- 99b-5p in breast cancer were analyzed using The Cancer Genome Atlas (TCGA) database. BT-474 cells were transfected with miR-99b-5p mimics and inhibitors, followed by treatment with tamoxifen and trastuzumab to assess their impact on cell proliferation and ER-HER2/EGFR crosstalk. Western blotting was performed to quantify EGFR, HER2, and ESR1 protein levels. Real-time proliferation analysis evaluated changes in cell growth following miRNA transfection and drug treatment. Results The study revealed that miR-99b-5p is significantly overexpressed in tumors compared to normal tissues and is associated with poor patient survival and enhanced ER signaling. Transfection with miR-99b-5p mimics increased ESR1 expression and cell proliferation, even in the presence of tamoxifen or trastuzumab, indicating that miR-99b-5p contributes to therapy resistance through receptor crosstalk. Conversely, miR-99b-5p inhibition significantly restored drug sensitivity, reducing proliferation and enhancing the effectiveness of tamoxifen and trastuzumab. Conclusion These findings establish miR-99b-5p as a key regulator of endocrine and HER2-targeted therapy resistance. Targeting miR-99b-5p could represent a potential therapeutic strategy to improve treatment outcomes in ER+/HER2+ breast cancer. Further research is needed to clarify the underlying molecular mechanisms and validate the therapeutic potential of miR-99b-5p inhibition in clinical applications.
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Affiliation(s)
- Senem Noyan
- Biotechnology Institute Ankara University, Ankara, Türkiye
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Porcaro F, Paolucci A, Porcaro P, Cardinale G, Romitelli A, Cozzolino D, Voccola S. Minimally Invasive and Emerging Diagnostic Approaches in Endometrial Cancer: Epigenetic Insights and the Promise of DNA Methylation. Diagnostics (Basel) 2024; 14:2575. [PMID: 39594241 PMCID: PMC11592808 DOI: 10.3390/diagnostics14222575] [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: 10/04/2024] [Revised: 11/08/2024] [Accepted: 11/14/2024] [Indexed: 11/28/2024] Open
Abstract
Endometrial cancer (EC) is the most common gynecological malignancy, with rising incidence and mortality rates. Key risk factors, including obesity, prolonged estrogen exposure, and metabolic disorders, underscore the urgent need for non-invasive, early diagnostic tools. This review focuses on the role of DNA methylation as a potential biomarker for early EC detection. Aberrant DNA methylation in the promoter regions of tumor suppressor genes can lead to gene silencing and cancer progression. We examine recent studies utilizing minimally invasive samples, such as urine, cervicovaginal, and cervical scrapes, to detect early-stage EC through DNA methylation patterns. Markers such as RASSF1A, HIST1H4F, GHSR, SST, and ZIC1 have demonstrated high diagnostic accuracy, with AUC values up to 0.95, effectively distinguishing EC from non-cancerous conditions. This review highlights the potential of DNA methylation-based testing as a non-invasive alternative to traditional diagnostic methods, offering earlier detection, better risk stratification, and more personalized treatment plans. These innovations hold the promise of transforming clinical practice by enabling more timely and effective management of endometrial cancer.
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Affiliation(s)
- Floriana Porcaro
- Centro Medico Delta S.r.l., 82030 Apollosa, Italy; (F.P.); (P.P.)
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Chen C, Tseng J, Amersi F, Silberman AW. Second primary malignancies in women with breast cancer. J Surg Oncol 2024; 130:355-359. [PMID: 39031014 DOI: 10.1002/jso.27785] [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: 04/05/2024] [Revised: 06/04/2024] [Accepted: 06/25/2024] [Indexed: 07/22/2024]
Abstract
BACKGROUND Increased screening and treatment advancements have resulted in improved survival rates in women with breast cancer (BC). However, recent data suggests these women have elevated risk of developing a second primary malignancy (SPM) compared to the general population. Limited data exists on factors associated with BC patients developing a SPM. METHOD A retrospective review of a prospective single institution database (1990-2016) identified 782 patients with a history of BC. One hundred and ninety-four BC patients developed a SPM. Clinicopathologic and treatment characteristics were analyzed. RESULTS Of the 194 patients (24.8%) who developed a SPM, 56 (28.9%) BC patients were <50 years old (range: 24-87 years). Two-thirds (64.9%) had at least one first or second degree relative with a malignancy (no relatives-35.1%; ≥1 relative-62.9%). Most patients had invasive ductal carcinoma (n = 117, 60.3%) or ductal carcinoma in situ (n = 39, 20.1%). Twenty-two patients (11.3%) had pathogenic genetic mutations. Mean time to developing a SPM was 8.9 years (range: 4 months-50 years). Eighty (47.6%) patients received chemotherapy with 91 (54.5%) completing radiation. The most common SPMs were breast (22%), melanoma (17.8%), gynecologic (14.1%), colorectal (12.6%), hematologic (8.9%), and sarcoma (6.5%). Most breast tumors were estrogen receptor (ER) (n = 99, 78.0%) or progesterone receptor (PR) positive (n = 87, 73.1%) but not HER2-neu positive (n = 13, 14.0%). CONCLUSION Most BC patients who developed a SPM had ER/PR positive tumors and a family history of malignancy, with most <50 years old. Although chemotherapy and radiation increase cancer risk, there were an equal number of patients with SPMs who did or did not receive either treatment. Most SPMs were breast, soft tissue, gynecologic, hematologic, or colorectal. BC patients should be followed closely given an elevated propensity for developing SPMs.
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MESH Headings
- Humans
- Female
- Neoplasms, Second Primary/epidemiology
- Neoplasms, Second Primary/pathology
- Middle Aged
- Breast Neoplasms/pathology
- Breast Neoplasms/therapy
- Breast Neoplasms/genetics
- Adult
- Aged
- Aged, 80 and over
- Retrospective Studies
- Young Adult
- Carcinoma, Ductal, Breast/pathology
- Carcinoma, Ductal, Breast/therapy
- Carcinoma, Ductal, Breast/epidemiology
- Carcinoma, Ductal, Breast/genetics
- Prospective Studies
- Follow-Up Studies
- Risk Factors
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Affiliation(s)
- Courtney Chen
- Department of Surgery, Cedars-Sinai Medical Center, Division of Surgical Oncology, Los Angeles, CA, USA
| | - Joshua Tseng
- Department of Surgery, Cedars-Sinai Medical Center, Division of Surgical Oncology, Los Angeles, CA, USA
| | - Farin Amersi
- Department of Surgery, Cedars-Sinai Medical Center, Division of Surgical Oncology, Los Angeles, CA, USA
| | - Allan W Silberman
- Department of Surgery, Cedars-Sinai Medical Center, Division of Surgical Oncology, Los Angeles, CA, USA
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Pan L, Li J, Xu Q, Gao Z, Yang M, Wu X, Li X. HER2/PI3K/AKT pathway in HER2-positive breast cancer: A review. Medicine (Baltimore) 2024; 103:e38508. [PMID: 38875362 PMCID: PMC11175886 DOI: 10.1097/md.0000000000038508] [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: 03/07/2024] [Revised: 05/01/2024] [Accepted: 05/17/2024] [Indexed: 06/16/2024] Open
Abstract
Breast cancer is currently the most commonly occurring cancer globally. Among breast cancer cases, the human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for 15% to 20% and is a crucial focus in the treatment of breast cancer. Common HER2-targeted drugs approved for treating early and/or advanced breast cancer include trastuzumab and pertuzumab, which effectively improve patient prognosis. However, despite treatment, most patients with terminal HER2-positive breast cancer ultimately suffer death from the disease due to primary or acquired drug resistance. The prevalence of aberrantly activated the protein kinase B (AKT) signaling in HER2-positive breast cancer was already observed in previous studies. It is well known that p-AKT expression is linked to an unfavorable prognosis, and the phosphatidylinositol-3-kinase (PI3K)/AKT pathway, as the most common mutated pathway in breast cancer, plays a major role in the mechanism of drug resistance. Therefore, in the current review, we summarize the molecular alterations present in HER2-positive breast cancer, elucidate the relationships between HER2 overexpression and alterations in the PI3K/AKT signaling pathway and the pathways of the alterations in breast cancer, and summarize the resistant mechanism of drugs targeting the HER2-AKT pathway, which will provide an adjunctive therapeutic rationale for subsequent resistance to directed therapy in the future.
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Affiliation(s)
- Linghui Pan
- Institute for Cancer Medicine and School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Jinling Li
- Institute for Cancer Medicine and School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
- Department of Laboratory Medicine, Chonggang General Hospital, Chongqing, China
| | - Qi Xu
- Institute for Cancer Medicine and School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Zili Gao
- Institute for Cancer Medicine and School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Mao Yang
- Institute for Cancer Medicine and School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Xiaoping Wu
- Institute for Cancer Medicine and School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Xuesen Li
- Institute for Cancer Medicine and School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
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Yan S, Ji J, Zhang Z, Imam M, Chen H, Zhang D, Wang J. Targeting the crosstalk between estrogen receptors and membrane growth factor receptors in breast cancer treatment: Advances and opportunities. Biomed Pharmacother 2024; 175:116615. [PMID: 38663101 DOI: 10.1016/j.biopha.2024.116615] [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: 01/10/2024] [Revised: 04/06/2024] [Accepted: 04/17/2024] [Indexed: 06/03/2024] Open
Abstract
Estrogens play a critical role in the initiation and progression of breast cancer. Estrogen receptor (ER)α, ERβ, and G protein-coupled estrogen receptor are the primary receptors for estrogen in breast cancer. These receptors are mainly activated by binding with estrogens. The crosstalk between ERs and membrane growth factor receptors creates additional pathways that amplify the effects of their ligands and promote tumor growth. This crosstalk may cause endocrine therapy resistance in ERα-positive breast cancer. Furthermore, this may explain the resistance to anti-human epidermal growth factor receptor-2 (HER2) treatment in ERα-/HER2-positive breast cancer and chemotherapy resistance in triple-negative breast cancer. Accordingly, it is necessary to understand the complex crosstalk between ERs and growth factor receptors. In this review, we delineate the crosstalk between ERs and membrane growth factor receptors in breast cancer. Moreover, this review highlights the current progress in clinical treatment and discusses how pharmaceuticals target the crosstalk. Lastly, we discuss the current challenges and propose potential solutions regarding the implications of targeting crosstalk via pharmacological inhibition. Overall, the present review provides a landscape of the crosstalk between ERs and membrane growth factor receptors in breast cancer, along with valuable insights for future studies and clinical treatments using a chemotherapy-sparing regimen to improve patient quality of life.
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Affiliation(s)
- Shunchao Yan
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, China.
| | - Jiale Ji
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, China
| | - Zhijie Zhang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, China
| | - Murshid Imam
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, China
| | - Hong Chen
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, China
| | - Duo Zhang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, China
| | - Jinpeng Wang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, China
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Feng D, Wang J, Xiao Y, Wu R, Li D, Tuo Z, Yu Q, Ye L, MIYAMOTO A, Yoo KH, Wei W, Ye X, Zhang C, Han P. SKA3 targeted therapies in cancer precision surgery: bridging bench discoveries to clinical applications - review article. Int J Surg 2024; 110:2323-2337. [PMID: 38241327 PMCID: PMC11020031 DOI: 10.1097/js9.0000000000001123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 01/09/2024] [Indexed: 01/21/2024]
Abstract
Spindle and kinetochore-associated complex subunit 3 (SKA3) is a microtubule-binding subcomplex of the outer kinetochore, which plays a vital role in proper chromosomal segregation and cell division. Recently, SKA3 have been demonstrated its oncogenic role of tumorigenesis and development in cancers. In this review, the authors comprehensively deciphered SKA3 in human cancer from various aspects, including bibliometrics, pan-cancer analysis, and narrative summary. The authors also provided the top 10 predicted drugs targeting SKA3. The authors proposed that SKA3 was a potential target and brought new therapeutic opportunities for cancer patients.
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Affiliation(s)
- Dechao Feng
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu
- Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Luzhou
| | - Jie Wang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu
| | - Yuhan Xiao
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu
| | - Ruicheng Wu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu
| | - Dengxiong Li
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu
| | - Zhouting Tuo
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei
| | - Qingxin Yu
- Department of Pathology, Ningbo Clinical Pathology Diagnosis Center, Ningbo City, Zhejiang Province
| | - Luxia Ye
- Department of Public Research Platform, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, People’s Republic of China
| | - Akira MIYAMOTO
- Department of Rehabilitation, West Kyushu University, Japan
| | - Koo Han Yoo
- Department of Urology, Kyung Hee University, South Korea
| | - Wuran Wei
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu
| | - Xing Ye
- Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Chi Zhang
- Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Luzhou
| | - Ping Han
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu
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McGrath MK, Abolhassani A, Guy L, Elshazly AM, Barrett JT, Mivechi NF, Gewirtz DA, Schoenlein PV. Autophagy and senescence facilitate the development of antiestrogen resistance in ER positive breast cancer. Front Endocrinol (Lausanne) 2024; 15:1298423. [PMID: 38567308 PMCID: PMC10986181 DOI: 10.3389/fendo.2024.1298423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 02/26/2024] [Indexed: 04/04/2024] Open
Abstract
Estrogen receptor positive (ER+) breast cancer is the most common breast cancer diagnosed annually in the US with endocrine-based therapy as standard-of-care for this breast cancer subtype. Endocrine therapy includes treatment with antiestrogens, such as selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs). Despite the appreciable remission achievable with these treatments, a substantial cohort of women will experience primary tumor recurrence, subsequent metastasis, and eventual death due to their disease. In these cases, the breast cancer cells have become resistant to endocrine therapy, with endocrine resistance identified as the major obstacle to the medical oncologist and patient. To combat the development of endocrine resistance, the treatment options for ER+, HER2 negative breast cancer now include CDK4/6 inhibitors used as adjuvants to antiestrogen treatment. In addition to the dysregulated activity of CDK4/6, a plethora of genetic and biochemical mechanisms have been identified that contribute to endocrine resistance. These mechanisms, which have been identified by lab-based studies utilizing appropriate cell and animal models of breast cancer, and by clinical studies in which gene expression profiles identify candidate endocrine resistance genes, are the subject of this review. In addition, we will discuss molecular targeting strategies now utilized in conjunction with endocrine therapy to combat the development of resistance or target resistant breast cancer cells. Of approaches currently being explored to improve endocrine treatment efficacy and patient outcome, two adaptive cell survival mechanisms, autophagy, and "reversible" senescence, are considered molecular targets. Autophagy and/or senescence induction have been identified in response to most antiestrogen treatments currently being used for the treatment of ER+ breast cancer and are often induced in response to CDK4/6 inhibitors. Unfortunately, effective strategies to target these cell survival pathways have not yet been successfully developed. Thus, there is an urgent need for the continued interrogation of autophagy and "reversible" senescence in clinically relevant breast cancer models with the long-term goal of identifying new molecular targets for improved treatment of ER+ breast cancer.
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Affiliation(s)
- Michael K. McGrath
- Georgia Cancer Center, Augusta University, Augusta, GA, United States
- Department of Cellular Biology & Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Ali Abolhassani
- Georgia Cancer Center, Augusta University, Augusta, GA, United States
- Department of Cellular Biology & Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Luke Guy
- Georgia Cancer Center, Augusta University, Augusta, GA, United States
- Department of Cellular Biology & Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Ahmed M. Elshazly
- Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, United States
- Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, United States
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt
| | - John T. Barrett
- Georgia Cancer Center, Augusta University, Augusta, GA, United States
- Department of Radiation Oncology, Georgia Cancer Center, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Nahid F. Mivechi
- Georgia Cancer Center, Augusta University, Augusta, GA, United States
- Department of Radiation Oncology, Georgia Cancer Center, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - David A. Gewirtz
- Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, United States
- Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, United States
| | - Patricia V. Schoenlein
- Georgia Cancer Center, Augusta University, Augusta, GA, United States
- Department of Cellular Biology & Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States
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Ding W, Ye D, Chen H, Lin Y, Li Z, Tu C. Clinicopathological differences and survival benefit in ER+/PR+/HER2+ vs ER+/PR-/HER2+ breast cancer subtypes. Breast Cancer 2024; 31:295-304. [PMID: 38231460 DOI: 10.1007/s12282-023-01538-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Accepted: 12/13/2023] [Indexed: 01/18/2024]
Abstract
INTRODUCTION Breast cancer subtypes based on estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression have significant implications for prognosis. HER2-positive tumors historically demonstrated poorer survival, but anti-HER2 targeted therapy improved outcomes. However, hormone receptor (HR)-positive patients may experience reduced benefit due to HER2-HR signaling crosstalk. METHODS Data from two databases, the Shanghai Jiao Tong University Breast Cancer Data Base (SJTUBCDB) and the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database, were analyzed. Propensity score adjustments were used to balance patient characteristics between ER+/PR+/HER2+ and ER+/PR-/HER2+ subtypes. Kaplan-Meier survival curves estimated disease-free survival (DFS), breast cancer-specific survival (BCSS), overall survival (OS) for these subtypes in the SJTUBCDB, while subgroup analyses using multivariable models were performed based on menstruation, pN stage, HER2-targeted therapy, and endocrinotherapy. RESULTS The ER+/PR+/HER2+ group showed significantly better DFS and BCSS than the ER+/PR-/HER2+ group, particularly in postmenopausal and pN0 stage patients. Survival outcomes were similar after anti-HER2 therapy or endocrine aromatase inhibitor (AI) therapy in both groups. However, among patients receiving selective estrogen receptor modulator (SERM) treatment, those in the ER+/PR-/HER2+ group had a significantly worse prognosis compared to ER+/PR+/HER2+ patients. CONCLUSIONS HER2-positive breast cancers with different HR statuses exhibit distinct clinicopathological features and survival outcomes. Patients in the ER+/PR+/HER2+ group generally experience better survival, particularly in postmenopausal and pN0 stage patients. Treatment strategies should consider HR status and specific modalities for better personalized management.
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Affiliation(s)
- Wu Ding
- Department of Oncological Surgery, Shaoxing Second Hospital, Shaoxing, 312000, China
- Department of Clinical Medicine, Shaoxing University School of Medicine, Shaoxing, China
| | - Dengfeng Ye
- Department of Oncological Surgery, Shaoxing Second Hospital, Shaoxing, 312000, China
| | - Haifeng Chen
- Department of Oncological Surgery, Shaoxing Second Hospital, Shaoxing, 312000, China
| | - Yingli Lin
- Department of Early Childhood Education, Shaoxing Vocational and Technical College, Shaoxing, China
| | - Zhian Li
- Department of Oncological Surgery, Shaoxing Second Hospital, Shaoxing, 312000, China.
| | - Chuanjian Tu
- Department of Surgery, Shaoxing Second Hospital, Shaoxing, 312000, China.
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Yu Q, Xu C, Song J, Jin Y, Gao X. Mechanisms of Traditional Chinese medicine/natural medicine in HR-positive Breast Cancer: A comprehensive Literature Review. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117322. [PMID: 37866466 DOI: 10.1016/j.jep.2023.117322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 09/13/2023] [Accepted: 10/12/2023] [Indexed: 10/24/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE With the emergence of endocrine resistance, the survival and good prognosis of HR-positive breast cancer (HR + BC) patients are threatened. As a common complementary and alternative therapy in cancer treatment, traditional Chinese medicine (TCM) has been widely used, and its internal mechanisms have been increasingly explored. AIM OF THE REVIEW In this review, the development status and achievements in understanding of the mechanisms related to the anti-invasion and anti-metastasis effects of TCM against HR + BC and the reversal of endocrine drug resistance by TCM in recent years have been summarized to provide ideas for antitumour research on the active components of TCM/natural medicine. METHODS We searched the electronic databases PubMed, Web of Science, and China National Knowledge Infrastructure database (CNKI) (from inception to July 2023) with the key words "HR-positive breast cancer" or "HR-positive breast carcinoma", "HR + BC" and "traditional Chinese medicine", "TCM", or "natural plant", "herb", etc., with the aim of elucidating the intrinsic mechanisms of traditional Chinese medicine and natural medicine in the treatment of HR + BC. RESULTS TCM/natural medicine monomers and formulas can regulate the expression of related genes and proteins through the PI3K/AKT, JAK2/STAT3, MAPK, Wnt and other signalling pathways, inhibit the proliferation and metastasis of HR + BC tumours, play a synergistic role in combination with endocrine drugs, and reverse endocrine drug resistance. CONCLUSION The wide variety of TCM/natural medicine components makes the research and development of new methods of TCM for BC treatments more selective and innovative. Although progress has been made on research on TCM/natural medicine, there are still many problems in clinical and basic experimental designs, and more in-depth scientific explorations and research are still needed.
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Affiliation(s)
- Qinghong Yu
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China.
| | - Chuchu Xu
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China.
| | - Jiaqing Song
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China.
| | - Ying Jin
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China.
| | - Xiufei Gao
- The First Affiliated Hospital of Zhejiang Chinese Medical University, NO. 54 Youdian Road, Hangzhou, Zhejiang, 310006, China.
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11
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Bahnassy S, Stires H, Jin L, Tam S, Mobin D, Balachandran M, Podar M, McCoy MD, Beckman RA, Riggins RB. Unraveling Vulnerabilities in Endocrine Therapy-Resistant HER2+/ER+ Breast Cancer. Endocrinology 2023; 164:bqad159. [PMID: 37897495 PMCID: PMC10651073 DOI: 10.1210/endocr/bqad159] [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: 08/21/2023] [Revised: 10/01/2023] [Accepted: 10/26/2023] [Indexed: 10/30/2023]
Abstract
Breast tumors overexpressing human epidermal growth factor receptor (HER2) confer intrinsic resistance to endocrine therapy (ET), and patients with HER2/estrogen receptor-positive (HER2+/ER+) breast cancer (BCa) are less responsive to ET than HER2-/ER+. However, real-world evidence reveals that a large subset of patients with HER2+/ER+ receive ET as monotherapy, positioning this treatment pattern as a clinical challenge. In the present study, we developed and characterized 2 in vitro models of ET-resistant (ETR) HER2+/ER+ BCa to identify possible therapeutic vulnerabilities. To mimic ETR to aromatase inhibitors (AIs), we developed 2 long-term estrogen deprivation (LTED) cell lines from BT-474 (BT474) and MDA-MB-361 (MM361). Growth assays, PAM50 subtyping, and genomic and transcriptomic analyses, followed by validation and functional studies, were used to identify targetable differences between ET-responsive parental and ETR-LTED HER2+/ER+ cells. Compared to their parental cells, MM361 LTEDs grew faster, lost ER, and increased HER2 expression, whereas BT474 LTEDs grew slower and maintained ER and HER2 expression. Both LTED variants had reduced responsiveness to fulvestrant. Whole-genome sequencing of aggressive MM361 LTEDs identified mutations in genes encoding transcription factors and chromatin modifiers. Single-cell RNA sequencing demonstrated a shift towards non-luminal phenotypes, and revealed metabolic remodeling of MM361 LTEDs, with upregulated lipid metabolism and ferroptosis-associated antioxidant genes, including GPX4. Combining a GPX4 inhibitor with anti-HER2 agents induced significant cell death in both MM361 and BT474 LTEDs. The BT474 and MM361 AI-resistant models capture distinct phenotypes of HER2+/ER+ BCa and identify altered lipid metabolism and ferroptosis remodeling as vulnerabilities of this type of ETR BCa.
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Affiliation(s)
- Shaymaa Bahnassy
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
| | | | - Lu Jin
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
| | - Stanley Tam
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
| | - Dua Mobin
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
| | - Manasi Balachandran
- Department of Medicine, University of Tennessee Medical Center, Knoxville, TN 37920, USA
| | - Mircea Podar
- Oak Ridge National Laboratory, Oak Ridge, TN 37830, USA
| | - Matthew D McCoy
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
| | - Robert A Beckman
- Department of Oncology and of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University Medical Center, Washington, DC 20007, USA
- Lombardi Comprehensive Cancer Center and Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington, DC 20007, USA
| | - Rebecca B Riggins
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
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12
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Atallah NM, Alsaleem M, Toss MS, Mongan NP, Rakha E. Differential response of HER2-positive breast cancer to anti-HER2 therapy based on HER2 protein expression level. Br J Cancer 2023; 129:1692-1705. [PMID: 37740038 PMCID: PMC10646129 DOI: 10.1038/s41416-023-02426-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 08/25/2023] [Accepted: 09/05/2023] [Indexed: 09/24/2023] Open
Abstract
BACKGROUND Increasing data indicate that HER2-positive (HER2 + ) breast cancer (BC) subtypes exhibit differential responses to targeted anti-HER2 therapy. This study aims to investigate these differences and the potential underlying molecular mechanisms. METHODS A large cohort of BC patients (n = 7390) was utilised. The clinicopathological characteristics and differential gene expression (DGE) of HER2+ immunohistochemical (IHC) subtypes, specifically HER2 IHC 3+ and IHC 2 + /Amplified, were assessed and correlated with pathological complete response (pCR) and survival in the neoadjuvant and adjuvant settings, respectively. The role of oestrogen receptor (ER) status was also investigated. RESULTS Compared to HER2 IHC 3+ tumours, BC patients with IHC 2 + /Amplified showed a significantly lower pCR rate (22% versus 57%, P < 0.001), shorter survival regardless of HER2 gene copy number, were less classified as HER2 enriched, and enriched for trastuzumab resistance and ER signalling pathway genes. ER positivity significantly decreased response to anti-HER2 therapy in IHC 2 + /Amplified, but not in IHC 3 + BC patients. CONCLUSION In HER2 + BC, overexpression of HER2 protein is the driver of the oncogenic pathway, and it is the main predictor of response to anti-HER2 therapy. ER signalling pathways are more dominant in BC with equivocal HER2 expression. personalised anti-HER2 therapy based on IHC classes should be considered.
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Affiliation(s)
- N M Atallah
- Division of Cancer and Stem Cells, School of Medicine, the University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, UK
- Department of Pathology, Faculty of Medicine, Menoufia University, Shibin el Kom, Egypt
| | - M Alsaleem
- Unit of Scientific Research, Applied College, Qassim University, Buraydah, Saudi Arabia
| | - M S Toss
- Histopathology Department, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - N P Mongan
- School of Veterinary Medicine and Sciences, University of Nottingham, Sutton Bonington, UK
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, 10065, USA
| | - E Rakha
- Division of Cancer and Stem Cells, School of Medicine, the University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, UK.
- Department of Pathology, Faculty of Medicine, Menoufia University, Shibin el Kom, Egypt.
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13
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da Silva FC, Brandão DC, Ferreira EA, Siqueira RP, Ferreira HSV, Da Silva Filho AA, Araújo TG. Tailoring Potential Natural Compounds for the Treatment of Luminal Breast Cancer. Pharmaceuticals (Basel) 2023; 16:1466. [PMID: 37895937 PMCID: PMC10610388 DOI: 10.3390/ph16101466] [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: 08/29/2023] [Revised: 09/24/2023] [Accepted: 09/29/2023] [Indexed: 10/29/2023] Open
Abstract
Breast cancer (BC) is the most diagnosed cancer worldwide, mainly affecting the epithelial cells from the mammary glands. When it expresses the estrogen receptor (ER), the tumor is called luminal BC, which is eligible for endocrine therapy with hormone signaling blockade. Hormone therapy is essential for the survival of patients, but therapeutic resistance has been shown to be worrying, significantly compromising the prognosis. In this context, the need to explore new compounds emerges, especially compounds of plant origin, since they are biologically active and particularly promising. Natural products are being continuously screened for treating cancer due to their chemical diversity, reduced toxicity, lower side effects, and low price. This review summarizes natural compounds for the treatment of luminal BC, emphasizing the activities of these compounds in ER-positive cells. Moreover, their potential as an alternative to endocrine resistance is explored, opening new opportunities for the design of optimized therapies.
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Affiliation(s)
- Fernanda Cardoso da Silva
- Laboratory of Genetics and Biotechnology, Institute of Biotechnology, Universidade Federal de Uberlândia, Patos de Minas 38700-002, MG, Brazil; (F.C.d.S.); (D.C.B.); (R.P.S.); (H.S.V.F.)
| | - Douglas Cardoso Brandão
- Laboratory of Genetics and Biotechnology, Institute of Biotechnology, Universidade Federal de Uberlândia, Patos de Minas 38700-002, MG, Brazil; (F.C.d.S.); (D.C.B.); (R.P.S.); (H.S.V.F.)
| | - Everton Allan Ferreira
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Juiz de Fora 36036-900, MG, Brazil; (E.A.F.); (A.A.D.S.F.)
| | - Raoni Pais Siqueira
- Laboratory of Genetics and Biotechnology, Institute of Biotechnology, Universidade Federal de Uberlândia, Patos de Minas 38700-002, MG, Brazil; (F.C.d.S.); (D.C.B.); (R.P.S.); (H.S.V.F.)
| | - Helen Soares Valença Ferreira
- Laboratory of Genetics and Biotechnology, Institute of Biotechnology, Universidade Federal de Uberlândia, Patos de Minas 38700-002, MG, Brazil; (F.C.d.S.); (D.C.B.); (R.P.S.); (H.S.V.F.)
| | - Ademar Alves Da Silva Filho
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Juiz de Fora 36036-900, MG, Brazil; (E.A.F.); (A.A.D.S.F.)
| | - Thaise Gonçalves Araújo
- Laboratory of Genetics and Biotechnology, Institute of Biotechnology, Universidade Federal de Uberlândia, Patos de Minas 38700-002, MG, Brazil; (F.C.d.S.); (D.C.B.); (R.P.S.); (H.S.V.F.)
- Laboratory of Nanobiotechnology Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia 38405-302, MG, Brazil
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14
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Will M, Liang J, Metcalfe C, Chandarlapaty S. Therapeutic resistance to anti-oestrogen therapy in breast cancer. Nat Rev Cancer 2023; 23:673-685. [PMID: 37500767 PMCID: PMC10529099 DOI: 10.1038/s41568-023-00604-3] [Citation(s) in RCA: 60] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/29/2023] [Indexed: 07/29/2023]
Abstract
The hormone receptor oestrogen receptor-α (ER) orchestrates physiological mammary gland development, breast carcinogenesis and the progression of breast tumours into lethal, treatment-refractory systemic disease. Selective antagonism of ER signalling has been one of the most successful therapeutic approaches in oncology, benefiting patients as both a cancer preventative measure and a cancer treatment strategy. However, resistance to anti-oestrogen therapy is a major clinical challenge. Over the past decade, we have gained an understanding of how breast cancers evolve under the pressure of anti-oestrogen therapy. This is best depicted by the case of oestrogen-independent mutations in the gene encoding ER (ESR1), which are virtually absent in primary breast cancer but highly prevalent (20-40%) in anti-oestrogen-treated metastatic disease. These and other findings highlight the 'evolvability' of ER+ breast cancer and the need to understand molecular processes by which this evolution occurs. Recent development and approval of next-generation ER antagonists to target ESR1-mutant breast cancer underscores the clinical importance of this evolvability and sets a new paradigm for the treatment of ER+ breast cancers.
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Affiliation(s)
- Marie Will
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jackson Liang
- Department of Oncology Biomarker Development, Genentech, South San Francisco, CA, USA
| | - Ciara Metcalfe
- Department of Discovery Oncology, Genentech, South San Francisco, CA, USA.
| | - Sarat Chandarlapaty
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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15
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Siatis KE, Giannopoulou E, Manou D, Sarantis P, Karamouzis MV, Raftopoulou S, Fasseas K, Alzahrani FM, Kalofonos HP, Theocharis AD. Resistance to hormone therapy in breast cancer cells promotes autophagy and EGFR signaling pathway. Am J Physiol Cell Physiol 2023; 325:C708-C720. [PMID: 37575061 PMCID: PMC10625825 DOI: 10.1152/ajpcell.00199.2023] [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: 05/09/2023] [Revised: 07/13/2023] [Accepted: 07/26/2023] [Indexed: 08/15/2023]
Abstract
Breast cancer is the leading cause of cancer deaths for women worldwide. Endocrine therapies represent the cornerstone for hormone-dependent breast cancer treatment. However, in many cases, endocrine resistance is induced with poor prognosis for patients. In the current study, we have developed MCF-7 cell lines resistant to fulvestrant (MCF-7Fulv) and tamoxifen (MCF-7Tam) aiming at investigating mechanisms underlying resistance. Both resistant cell lines exerted lower proliferation capacity in two-dimensional (2-D) cultures but retain estrogen receptor α (ERα) expression and proliferate independent of the presence of estrogens. The established cell lines tend to be more aggressive exhibiting advanced capacity to form colonies, increased expression of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and heterodimerization of ERBB family receptors and activation of EGFR downstream pathways like MEK/ERK1/2 and PI3K/AKT. Tyrosine kinase inhibitors tested against resistant MCF-7Fulv and MCF-7Tam cells showed moderate efficacy to inhibit cell proliferation, except for lapatinib, which concomitantly inhibits both EGFR and HER2 receptors and strongly reduced cell proliferation. Furthermore, increased autophagy was observed in resistant MCF-7Fulv and MCF-7Tam cells as shown by the presence of autophagosomes and increased Beclin-1 levels. The increased autophagy in resistant cells is not associated with increased apoptosis, suggesting a cytoprotective role for autophagy that may favor cells' survival and aggressiveness. Thus, by exploiting those underlying mechanisms, new targets could be established to overcome endocrine resistance.NEW & NOTEWORTHY The development of resistance to hormone therapy caused by both fulvestrant and tamoxifen promotes autophagy with concomitant apoptosis evasion, rendering cells capable of surviving and growing. The fact that resistance also triggers ERBB family signaling pathways, which are poorly inhibited by tyrosine kinase inhibitors might attribute to cells' aggressiveness. It is obvious that the development of endocrine therapy resistance involves a complex interplay between deregulated ERBB signaling and autophagy that may be considered in clinical practice.
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Affiliation(s)
- Konstantinos E Siatis
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Rio, Greece
- Clinical Oncology Laboratory, Division of Oncology, Department of Medicine, University of Patras, Rio, Greece
| | - Efstathia Giannopoulou
- Clinical Oncology Laboratory, Division of Oncology, Department of Medicine, University of Patras, Rio, Greece
| | - Dimitra Manou
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Rio, Greece
| | - Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Michalis V Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Sofia Raftopoulou
- Electron Microscopy Laboratory, Faculty of Crop Production, Agricultural University of Athens, Athens, Greece
| | - Konstantinos Fasseas
- Electron Microscopy Laboratory, Faculty of Crop Production, Agricultural University of Athens, Athens, Greece
| | - Fatimah Mohammed Alzahrani
- Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Haralabos P Kalofonos
- Clinical Oncology Laboratory, Division of Oncology, Department of Medicine, University of Patras, Rio, Greece
| | - Achilleas D Theocharis
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Rio, Greece
- Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
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16
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Bahnassy S, Stires H, Jin L, Tam S, Mobin D, Balachandran M, Podar M, McCoy MD, Beckman RA, Riggins RB. Unraveling Vulnerabilities in Endocrine Therapy-Resistant HER2+/ER+ Breast Cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.21.554116. [PMID: 37662291 PMCID: PMC10473676 DOI: 10.1101/2023.08.21.554116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2023]
Abstract
Background Breast tumors overexpressing human epidermal growth factor receptor (HER2) confer intrinsic resistance to endocrine therapy (ET), and patients with HER2/ estrogen receptor-positive (HER2+/HR+) breast cancer (BCa) are less responsive to ET than HER2-/ER+. However, real-world evidence reveals that a large subset of HER2+/ER+ patients receive ET as monotherapy, positioning this treatment pattern as a clinical challenge. In the present study, we developed and characterized two distinct in vitro models of ET-resistant (ETR) HER2+/ER+ BCa to identify possible therapeutic vulnerabilities. Methods To mimic ETR to aromatase inhibitors (AI), we developed two long-term estrogen-deprived (LTED) cell lines from BT-474 (BT474) and MDA-MB-361 (MM361). Growth assays, PAM50 molecular subtyping, genomic and transcriptomic analyses, followed by validation and functional studies, were used to identify targetable differences between ET-responsive parental and ETR-LTED HER2+/ER+ cells. Results Compared to their parental cells, MM361 LTEDs grew faster, lost ER, and increased HER2 expression, whereas BT474 LTEDs grew slower and maintained ER and HER2 expression. Both LTED variants had reduced responsiveness to fulvestrant. Whole-genome sequencing of the more aggressive MM361 LTED model system identified exonic mutations in genes encoding transcription factors and chromatin modifiers. Single-cell RNA sequencing demonstrated a shift towards non-luminal phenotypes, and revealed metabolic remodeling of MM361 LTEDs, with upregulated lipid metabolism and antioxidant genes associated with ferroptosis, including GPX4. Combining the GPX4 inhibitor RSL3 with anti-HER2 agents induced significant cell death in both the MM361 and BT474 LTEDs. Conclusions The BT474 and MM361 AI-resistant models capture distinct phenotypes of HER2+/ER+ BCa and identify altered lipid metabolism and ferroptosis remodeling as vulnerabilities of this type of ETR BCa.
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Affiliation(s)
- Shaymaa Bahnassy
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
| | | | - Lu Jin
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
| | - Stanley Tam
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
| | - Dua Mobin
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
| | - Manasi Balachandran
- Department of Medicine, University of Tennessee Medical Center, Knoxville, TN
| | | | - Matthew D. McCoy
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
| | - Robert A. Beckman
- Departments of Oncology and of Biostatistics, Bioinformatics, and Biomathematics, Lombardi Comprehensive Cancer Center and Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington, DC
| | - Rebecca B. Riggins
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
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17
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Schuster EF, Lopez-Knowles E, Alataki A, Zabaglo L, Folkerd E, Evans D, Sidhu K, Cheang MCU, Tovey H, Salto-Tellez M, Maxwell P, Robertson J, Smith I, Bliss JM, Dowsett M. Molecular profiling of aromatase inhibitor sensitive and resistant ER+HER2- postmenopausal breast cancers. Nat Commun 2023; 14:4017. [PMID: 37419892 PMCID: PMC10328947 DOI: 10.1038/s41467-023-39613-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 06/15/2023] [Indexed: 07/09/2023] Open
Abstract
Aromatase inhibitors (AIs) reduce recurrences and mortality in postmenopausal patients with oestrogen receptor positive (ER+) breast cancer (BC), but >20% of patients will eventually relapse. Given the limited understanding of intrinsic resistance in these tumours, here we conduct a large-scale molecular analysis to identify features that impact on the response of ER + HER2- BC to AI. We compare the 15% of poorest responders (PRs, n = 177) as measured by proportional Ki67 changes after 2 weeks of neoadjuvant AI to good responders (GRs, n = 190) selected from the top 50% responders in the POETIC trial and matched for baseline Ki67 categories. In this work, low ESR1 levels are associated with poor response, high proliferation, high expression of growth factor pathways and non-luminal subtypes. PRs having high ESR1 expression have similar proportions of luminal subtypes to GRs but lower plasma estradiol levels, lower expression of estrogen response genes, higher levels of tumor infiltrating lymphocytes and immune markers, and more TP53 mutations.
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Affiliation(s)
- Eugene F Schuster
- The Breast Cancer Now Toby Robins Research Centre at the Institute of Cancer Research, London, UK.
- Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital, London, UK.
| | - Elena Lopez-Knowles
- The Breast Cancer Now Toby Robins Research Centre at the Institute of Cancer Research, London, UK
- Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital, London, UK
| | - Anastasia Alataki
- The Breast Cancer Now Toby Robins Research Centre at the Institute of Cancer Research, London, UK
- Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital, London, UK
| | | | - Elizabeth Folkerd
- The Breast Cancer Now Toby Robins Research Centre at the Institute of Cancer Research, London, UK
- Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital, London, UK
| | | | | | - Maggie Chon U Cheang
- Clinical Trials and Statistics Unit, Division of Clinical Studies, The Institute of Cancer Research, London, UK
| | - Holly Tovey
- Clinical Trials and Statistics Unit, Division of Clinical Studies, The Institute of Cancer Research, London, UK
| | - Manuel Salto-Tellez
- Precision Medicine Centre of Excellence, The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
- Cellular Pathology, Belfast Health and Social Care Trust, Belfast City Hospital, Belfast, UK
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
| | - Perry Maxwell
- Precision Medicine Centre of Excellence, The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
| | - John Robertson
- Faculty of Medicine & Health Sciences, Queen's Medical Centre, Nottingham, UK
| | | | - Judith M Bliss
- Clinical Trials and Statistics Unit, Division of Clinical Studies, The Institute of Cancer Research, London, UK
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18
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Satpathi S, Gaurkar SS, Potdukhe A, Wanjari MB. Unveiling the Role of Hormonal Imbalance in Breast Cancer Development: A Comprehensive Review. Cureus 2023; 15:e41737. [PMID: 37575755 PMCID: PMC10415229 DOI: 10.7759/cureus.41737] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 07/11/2023] [Indexed: 08/15/2023] Open
Abstract
Breast cancer is a complex and multifactorial disease with a significant global impact. Hormonal imbalance has emerged as a crucial factor in breast cancer development, highlighting the importance of understanding the intricate interplay between hormones and breast tissue. This comprehensive review aims to unveil the role of hormonal imbalance in breast cancer by exploring the involvement of key hormones, including estrogen and progesterone, and their receptors in tumor development. The review delves into how hormonal imbalance impacts breast tissue, emphasizing the significance of hormone receptor status in guiding treatment decisions. Furthermore, the review investigates the influence of other hormones, such as insulin and growth factors, and their cross-talk with hormone pathways in breast cancer progression. The implications of hormonal imbalance assessment in breast cancer risk assessment and the importance of hormone testing in diagnosis and treatment decisions are also discussed. Moreover, the review provides an overview of the various hormonal therapies used in breast cancer treatment, their benefits, limitations, and ongoing research efforts to optimize their efficacy and overcome resistance. Future directions in hormonal therapy research, including developing novel therapies and personalized medicine approaches, are explored. This review underscores the need for a comprehensive understanding of hormonal imbalance in breast cancer to enhance prevention, diagnosis, and treatment strategies, ultimately improving outcomes for individuals affected by this disease.
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Affiliation(s)
- Shweta Satpathi
- Internal Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Sagar S Gaurkar
- Otolaryngology and Head and Neck Surgery, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Ashwini Potdukhe
- Medical Surgical Nursing, Srimati Radhikabai Meghe Memorial College of Nursing, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Mayur B Wanjari
- Research and Development, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
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19
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Khallouki F, Hajji L, Saber S, Bouddine T, Edderkaoui M, Bourhia M, Mir N, Lim A, El Midaoui A, Giesy JP, Aboul-Soud MAM, Silvente-Poirot S, Poirot M. An Update on Tamoxifen and the Chemo-Preventive Potential of Vitamin E in Breast Cancer Management. J Pers Med 2023; 13:jpm13050754. [PMID: 37240924 DOI: 10.3390/jpm13050754] [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: 04/08/2023] [Revised: 04/24/2023] [Accepted: 04/26/2023] [Indexed: 05/28/2023] Open
Abstract
Breast cancer (BC) is the most common female cancer in terms of incidence and mortality worldwide. Tamoxifen (Nolvadex) is a widely prescribed, oral anti-estrogen drug for the hormonal treatment of estrogen-receptor-positive BC, which represents 70% of all BC subtypes. This review assesses the current knowledge on the molecular pharmacology of tamoxifen in terms of its anticancer and chemo-preventive actions. Due to the importance of vitamin E compounds, which are widely taken as a supplementary dietary component, the review focuses only on the potential importance of vitamin E in BC chemo-prevention. The chemo-preventive and onco-protective effects of tamoxifen combined with the potential effects of vitamin E can alter the anticancer actions of tamoxifen. Therefore, methods involving an individually designed, nutritional intervention for patients with BC warrant further consideration. These data are of great importance for tamoxifen chemo-prevention strategies in future epidemiological studies.
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Affiliation(s)
- Farid Khallouki
- Biology Department, FSTE, Moulay Ismail University of Meknes, BP 609, Errachidia 52000, Morocco
- Biology Department, Faculty of Sciences, Moulay Ismail University of Meknes, BP. 11201 Zitoune, Meknes 50050, Morocco
| | - Lhoussain Hajji
- Biology Department, Faculty of Sciences, Moulay Ismail University of Meknes, BP. 11201 Zitoune, Meknes 50050, Morocco
| | - Somayya Saber
- Biology Department, FSTE, Moulay Ismail University of Meknes, BP 609, Errachidia 52000, Morocco
- Biology Department, Faculty of Sciences, Moulay Ismail University of Meknes, BP. 11201 Zitoune, Meknes 50050, Morocco
| | - Toufik Bouddine
- Biology Department, Faculty of Sciences, Moulay Ismail University of Meknes, BP. 11201 Zitoune, Meknes 50050, Morocco
| | - Mouad Edderkaoui
- Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center & University of California, Los Angeles, CA 90048, USA
| | - Mohammed Bourhia
- Higher Institute of Nursing Professions and Technical Health, Laayoune 70000, Morocco
| | - Nora Mir
- Biology Department, Faculty of Sciences, Moulay Ismail University of Meknes, BP. 11201 Zitoune, Meknes 50050, Morocco
| | - Adrian Lim
- Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center & University of California, Los Angeles, CA 90048, USA
| | - Adil El Midaoui
- Biology Department, FSTE, Moulay Ismail University of Meknes, BP 609, Errachidia 52000, Morocco
| | - John P Giesy
- Toxicology Centre, University of Saskatchewan, Saskatoon, SK S7N 5B3, Canada
- Department of Veterinary Biomedical Sciences, University of Saskatchewan, Saskatoon, SK S7N 5B4, Canada
- Department of Integrative Biology, Michigan State University, East Lansing, MI 48824, USA
- Department of Environmental Sciences, Baylor University, Waco, TX 76706, USA
| | - Mourad A M Aboul-Soud
- Medical and Molecular Genetics Research, Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh 11433, Saudi Arabia
| | - Sandrine Silvente-Poirot
- Cancer Research Center of Toulouse, UMR 1037 INSERM, UMR 5071 CNRS, University of Toulouse III, Equipe labellisée par la Ligue Nationale Contre le Cancer, 31037 Toulouse, France
- French Network for Nutrition And Cancer Research (NACRe Network), 78350 Jouy-en-Josas, France
| | - Marc Poirot
- Cancer Research Center of Toulouse, UMR 1037 INSERM, UMR 5071 CNRS, University of Toulouse III, Equipe labellisée par la Ligue Nationale Contre le Cancer, 31037 Toulouse, France
- French Network for Nutrition And Cancer Research (NACRe Network), 78350 Jouy-en-Josas, France
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20
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Xu Y, Liang Y, Yin G. Detecting the expression of HRs and BCL2 via IHC can help identify luminal A-like subtypes of triple-positive breast cancers. Clin Transl Oncol 2023; 25:1024-1032. [PMID: 36376700 DOI: 10.1007/s12094-022-03007-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 11/07/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND Triple-positive breast cancer (TPBC) is a tumor that simultaneously expresses estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). Luminal A-like TPBC is a special subtype with a favorable prognosis but benefits less from HER2-targeted therapy. However, little is known about how to identify luminal A-like TPBCs. Therefore, our study aims to explore a clinically feasible method to identify luminal A-like TPBCs using immunohistochemical (IHC) markers. METHODS Our cohort enrolled consecutive 190 patients with early-stage TPBCs diagnosed, treated and followed up in our hospital between 2013 and 2019. Patients whose IHC staining displayed ≥ 50% in both ER and PR scores and B-cell lymphoma 2 (BCL2) positivity were classified as cohort A (n = 64), and the rest were enrolled in cohort B (n = 126). Kaplan-Meier plotter and log-rank test were used to compare the survival difference between cohort A and cohort B and the efficacy of trastuzumab therapy in the two cohorts. RESULTS The disease-free survival (DFS) of patients in cohort A was significantly better than in cohort B (p = 0.031). In cohort A, there was no statistically significant difference in DFS between patients treated with trastuzumab and those without trastuzumab (p = 0.663). While in cohort B, patients treated with trastuzumab had significantly better DFS than those without trastuzumab (p = 0.032). Multivariate survival analysis showed that cohort A was associated with better DFS(95%CI 1.046-11.776, p = 0.042). CONCLUSION TPBCs consist of heterogeneous subtypes. Detecting the expression of ER, PR and BCL2 via IHC can help identify luminal A-like TPBCs. This study will enable individualized treatment of TPBCs.
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Affiliation(s)
- Yingying Xu
- Department of Breast Surgery, Second Hospital of Jilin University, Changchun, 130041, China
| | - Yonghao Liang
- Department of Breast Surgery, Second Hospital of Jilin University, Changchun, 130041, China
| | - Guanghao Yin
- Department of Breast Surgery, Second Hospital of Jilin University, Changchun, 130041, China.
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21
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Tecalco-Cruz AC, López-Canovas L, Azuara-Liceaga E. Estrogen signaling via estrogen receptor alpha and its implications for neurodegeneration associated with Alzheimer's disease in aging women. Metab Brain Dis 2023; 38:783-793. [PMID: 36640216 DOI: 10.1007/s11011-023-01161-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 01/05/2023] [Indexed: 01/15/2023]
Abstract
Estrogen receptor alpha (ERα) is a transcription factor activated by estrogenic hormones to regulate gene expression in certain organs, including the brain. In the brain, estrogen signaling pathways are central for maintaining cognitive functions. Herein, we review the neuroprotective effects of estrogens mediated by ERα. The estrogen/ERα pathways are affected by the reduction of estrogens in menopause, and this event may be a risk factor for neurodegeneration associated with Alzheimer's disease in women. Thus, developing a better understanding of estrogen/ERα signaling may be critical for defining new biomarkers and potential therapeutic targets for Alzheimer's disease in women.
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Affiliation(s)
- Angeles C Tecalco-Cruz
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México (UACM), Apdo, Postal 03100, Ciudad de México, Mexico.
| | - Lilia López-Canovas
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México (UACM), Apdo, Postal 03100, Ciudad de México, Mexico
| | - Elisa Azuara-Liceaga
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México (UACM), Apdo, Postal 03100, Ciudad de México, Mexico
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22
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Hagan ML, Mander S, Joseph C, Mcgrath M, Barrett A, Lewis A, Hill WD, Browning D, Mcgee-Lawrence ME, Cai H, Liu K, Barrett JT, Gewirtz DA, Thangaraju M, Schoenlein PV. Upregulation of the EGFR/MEK1/MAPK1/2 signaling axis as a mechanism of resistance to antiestrogen‑induced BimEL dependent apoptosis in ER + breast cancer cells. Int J Oncol 2022; 62:20. [PMID: 36524361 PMCID: PMC9854236 DOI: 10.3892/ijo.2022.5468] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 11/18/2022] [Indexed: 12/23/2022] Open
Abstract
The epidermal growth factor receptor (EGFR) is commonly upregulated in multiple cancer types, including breast cancer. In the present study, evidence is provided in support of the premise that upregulation of the EGFR/MEK1/MAPK1/2 signaling axis during antiestrogen treatment facilitates the escape of breast cancer cells from BimEL‑dependent apoptosis, conferring resistance to therapy. This conclusion is based on the findings that ectopic BimEL cDNA overexpression and confocal imaging studies confirm the pro‑apoptotic role of BimEL in ERα expressing breast cancer cells and that upregulated EGFR/MEK1/MAPK1/2 signaling blocks BimEL pro‑apoptotic action in an antiestrogen‑resistant breast cancer cell model. In addition, the present study identified a pro‑survival role for autophagy in antiestrogen resistance while EGFR inhibitor studies demonstrated that a significant percentage of antiestrogen‑resistant breast cancer cells survive EGFR targeting by pro‑survival autophagy. These pre‑clinical studies establish the possibility that targeting both the MEK1/MAPK1/2 signaling axis and pro‑survival autophagy may be required to eradicate breast cancer cell survival and prevent the development of antiestrogen resistance following hormone treatments. The present study uniquely identified EGFR upregulation as one of the mechanisms breast cancer cells utilize to evade the cytotoxic effects of antiestrogens mediated through BimEL‑dependent apoptosis.
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Affiliation(s)
- Mackenzie L. Hagan
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA 30912, USA
| | - Suchreet Mander
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA 30912, USA
| | - Carol Joseph
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA 30912, USA
| | - Michael Mcgrath
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA 30912, USA
| | - Amanda Barrett
- Department of Pathology, Augusta University, Augusta, GA 30912, USA,Department of Medical College of Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
| | - Allison Lewis
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA 30912, USA
| | - William D. Hill
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Darren Browning
- Department of Medical College of Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA,Department of Biochemistry, Augusta University, Augusta, GA 30912, USA
| | | | - Haifeng Cai
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA 30912, USA,Department of Surgical Oncology, Tangshan People's Hospital, Tangshan, Hebei 063000, P.R. China
| | - Kebin Liu
- Department of Medical College of Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA,Department of Biochemistry, Augusta University, Augusta, GA 30912, USA
| | - John T. Barrett
- Department of Medical College of Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA,Department of Radiation Oncology, Augusta University, Augusta, GA 30912, USA
| | - David A. Gewirtz
- Department of Pharmacology and Toxicology, Massey Cancer Center, Richmond, VA 23298, USA
| | - Muthusamy Thangaraju
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA 30912, USA,Department of Medical College of Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
| | - Patricia V. Schoenlein
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA 30912, USA,Department of Medical College of Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA,Correspondence to: Dr Patricia V. Schoenlein, Department of Cellular Biology and Anatomy, Augusta University, Research and Education Building Room 2912, 1120 15th Street, Augusta, GA 30912, USA, E-mail:
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23
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Chen WC, Hsu CC, Huang HJ, Cheng WJ, Chang TC, Chou HH. Letrozole as premedication of high intensity focused ultrasound treatment of uterine fibroids: A retrospective observation study. Front Med (Lausanne) 2022; 9:1069654. [PMID: 36561715 PMCID: PMC9763453 DOI: 10.3389/fmed.2022.1069654] [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: 10/14/2022] [Accepted: 11/21/2022] [Indexed: 12/12/2022] Open
Abstract
Background No reports on Letrozole as a pretreatment before ablation of uterine fibroid with high intensity focused ultrasound (HIFU), so a retrospective observation study was performed to evaluate the response of different pre-HIFU medication. Methods We collected patients with single uterine fibroid receiving HIFU ablation from January 2018 to April 2021. All enrolled patients were classified into three group: group A (no pre-HIFU medication use), group B (Pre-HIFU letrozole use), group C (pre-HIFU gonadotrophin releasing hormone analog, GnRHa). Further associated clinical data and treatment response after HIFU treatment were reviewed and evaluated. Results A total of 39 patients including 21, 7, and 11 in group A, B, and C were collected respectively. After pre-HIFU medication, no difference of fibroid volume was found (A: 251.4, B: 360.6, C: 409.4 cm3, p = 0.250), and GnRHa group had significantly larger volume reduction than Letrozole users (38.6% vs. 16.4%, p = 0.007). The incidence of hypoestrogenic symptoms was higher in GnRHa group than in letrozole users (27.3% vs. 0, p = 0.170). GnRHa group had more sonication time (p = 0.001), treatment duration (p = 0.002), and ablated energy (p = 0.001) than group A and B. The treatment efficiency was higher in letrozole group than that in other 2 groups (4.52 vs. 2.39 vs. 2.34 cm3/min, p = 0.050). For patients with fibroid over 10 cm in diameter, letrozole group had even better energy efficiency (p = 0.067), treatment speed (p = 0.007), treatment efficiency (p = 0.001), NPV per energy (p = 0.005), and NPV per sonication (p = 0.004) than other 2 groups. Conclusion Letrozole as a pretreatment medication before HIFU treatment might increase the energy efficiency and treatment efficiency of its ablation of uterine leiomyoma, especially for fibroid over 10 cm. Future study of larger patient number is needed to confirm our results.
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Affiliation(s)
- Wei-Chun Chen
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan,Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taoyuan, Taiwan,Department of Obstetrics and Gynecology, New Taipei City Municipal Tucheng Hospital, New Taipei City, Taiwan,High Intensity Focused Ultrasound (HIFU) Treatment Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan,College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chia-Chen Hsu
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Huei-Jean Huang
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taoyuan, Taiwan,High Intensity Focused Ultrasound (HIFU) Treatment Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Wei-Jen Cheng
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan,Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan,School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ting-Chang Chang
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taoyuan, Taiwan,High Intensity Focused Ultrasound (HIFU) Treatment Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan,College of Medicine, Chang Gung University, Taoyuan, Taiwan,*Correspondence: Ting-Chang Chang
| | - Hung-Hsueh Chou
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taoyuan, Taiwan,High Intensity Focused Ultrasound (HIFU) Treatment Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan,School of Medicine, National Tsing Hua University, Hsinchu, Taiwan,Hung-Hsueh Chou
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24
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Tewari S, Vargas R, Reizes O. The impact of obesity and adipokines on breast and gynecologic malignancies. Ann N Y Acad Sci 2022; 1518:131-150. [PMID: 36302117 PMCID: PMC10092047 DOI: 10.1111/nyas.14916] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The link between obesity and multiple disease comorbidities is well established. In 2003, Calle and colleagues presented the relationship between obesity and several cancer types, including breast, ovarian, and endometrial malignancies. Nearly, 20% of cancer-related deaths in females can be accounted for by obesity. Identifying obesity as a risk factor for cancer led to a focus on the role of fat-secreted cytokines, known as adipokines, on carcinogenesis and tumor progression. Early studies indicated that the adipokine leptin increases cell proliferation, invasion, and inhibition of apoptosis in multiple cancer types. As a greater appreciation of the obesity-cancer link has amassed, we now know that additional adipokines can impact tumorigenesis. A deeper understanding of the adipokine-activated signaling in cancer may identify new treatment strategies irrespective of obesity. Moreover, adipokines may serve as disease biomarkers, harnessing the potential of obesity-associated factors to serve as indicators of treatment response and disease prognosis. As studies investigating obesity and women's cancers continue to expand, it has become evident that breast, ovarian, and uterine cancers are distinctly impacted by adipokines. While complex, these distinct interactions may provide insight into cancer progression in these organs and new opportunities for targeted therapies. This review aims to organize and present the literature from the last 5 years investigating the mechanisms and implications of adipokine signaling in breast, endometrial, and ovarian cancers with a special focus on leptin and adiponectin.
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Affiliation(s)
- Surabhi Tewari
- Cleveland Clinic Lerner College of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Roberto Vargas
- Department of Gynecologic Oncology, Women's Health Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Case Comprehensive Cancer Center, Cleveland, Ohio, USA
| | - Ofer Reizes
- Department of Gynecologic Oncology, Women's Health Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Case Comprehensive Cancer Center, Cleveland, Ohio, USA.,Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
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25
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D'Urso S, Arumugam P, Weider T, Hwang LD, Bond TA, Kemp JP, Warrington NM, Evans DM, O'Mara TA, Moen GH. Mendelian randomization analysis of factors related to ovulation and reproductive function and endometrial cancer risk. BMC Med 2022; 20:419. [PMID: 36320039 PMCID: PMC9623961 DOI: 10.1186/s12916-022-02585-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 09/26/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Observational epidemiological studies suggest a link between several factors related to ovulation and reproductive function and endometrial cancer (EC) risk; however, it is not clear whether these relationships are causal, and whether the risk factors act independently of each other. The aim of this study was to investigate putative causal relationships between the number of live births, age at last live birth, and years ovulating and EC risk. METHODS: We conducted a series of observational analyses to investigate various risk factors and EC risk in the UK Biobank (UKBB). Additionally, multivariate analysis was performed to elucidate the relationship between the number of live births, age at last live birth, and years ovulating and other related factors such as age at natural menopause, age at menarche, and body mass index (BMI). Secondly, we used Mendelian randomization (MR) to assess if these observed relationships were causal. Genome-wide significant single nucleotide polymorphisms (SNPs) were extracted from previous studies of woman's number of live births, age at menopause and menarche, and BMI. We conducted a genome-wide association analysis using the UKBB to identify SNPs associated with years ovulating, years using the contraceptive pill, and age at last live birth. RESULTS We found evidence for a causal effect of the number of live births (inverse variance weighted (IVW) odds ratio (OR): 0.537, p = 0.006), the number of years ovulating (IVW OR: 1.051, p = 0.014), in addition to the known risk factors BMI, age at menarche, and age at menopause on EC risk in the univariate MR analyses. Due to the close relationships between these factors, we followed up with multivariable MR (MVMR) analysis. Results from the MVMR analysis showed that number of live births had a causal effect on EC risk (OR: 0.783, p = 0.036) independent of BMI, age at menarche and age at menopause. CONCLUSIONS MVMR analysis showed that the number of live births causally reduced the risk of EC.
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Affiliation(s)
- Shannon D'Urso
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
| | - Pooja Arumugam
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Australia
| | - Therese Weider
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway
| | - Liang-Dar Hwang
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
| | - Tom A Bond
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
- Bristol Medical School, Population Health Science, University of Bristol, Bristol, UK
- Department of Epidemiology and Biostatistics, Imperial College London, London, UK
| | - John P Kemp
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Nicole M Warrington
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
| | - David M Evans
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Tracy A O'Mara
- Cancer Research Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Gunn-Helen Moen
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
- The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia.
- Bristol Medical School, Population Health Science, University of Bristol, Bristol, UK.
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
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26
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Ozyurt R, Ozpolat B. Molecular Mechanisms of Anti-Estrogen Therapy Resistance and Novel Targeted Therapies. Cancers (Basel) 2022; 14:5206. [PMID: 36358625 PMCID: PMC9655708 DOI: 10.3390/cancers14215206] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/05/2022] [Accepted: 10/20/2022] [Indexed: 07/29/2023] Open
Abstract
Breast cancer (BC) is the most commonly diagnosed cancer in women, constituting one-third of all cancers in women, and it is the second leading cause of cancer-related deaths in the United States. Anti-estrogen therapies, such as selective estrogen receptor modulators, significantly improve survival in estrogen receptor-positive (ER+) BC patients, which represents about 70% of cases. However, about 60% of patients inevitably experience intrinsic or acquired resistance to anti-estrogen therapies, representing a major clinical problem that leads to relapse, metastasis, and patient deaths. The resistance mechanisms involve mutations of the direct targets of anti-estrogen therapies, compensatory survival pathways, as well as alterations in the expression of non-coding RNAs (e.g., microRNA) that regulate the activity of survival and signaling pathways. Although cyclin-dependent kinase 4/6 and phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitors have significantly improved survival, the efficacy of these therapies alone and in combination with anti-estrogen therapy for advanced ER+ BC, are not curative in advanced and metastatic disease. Therefore, understanding the molecular mechanisms causing treatment resistance is critical for developing highly effective therapies and improving patient survival. This review focuses on the key mechanisms that contribute to anti-estrogen therapy resistance and potential new treatment strategies alone and in combination with anti-estrogen drugs to improve the survival of BC patients.
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Affiliation(s)
- Rumeysa Ozyurt
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Houston Methodist Research Institute, Department of Nanomedicine, 6670 Bertner Ave, Houston, TX 77030, USA
| | - Bulent Ozpolat
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Houston Methodist Research Institute, Department of Nanomedicine, 6670 Bertner Ave, Houston, TX 77030, USA
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27
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Kuilman MM, Ellappalayam A, Barcaru A, Haan JC, Bhaskaran R, Wehkamp D, Menicucci AR, Audeh WM, Mittempergher L, Glas AM. BluePrint breast cancer molecular subtyping recognizes single and dual subtype tumors with implications for therapeutic guidance. Breast Cancer Res Treat 2022; 195:263-274. [PMID: 35984580 PMCID: PMC9464757 DOI: 10.1007/s10549-022-06698-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 07/27/2022] [Indexed: 12/05/2022]
Abstract
PURPOSE BluePrint (BP) is an 80-gene molecular subtyping test that classifies early-stage breast cancer (EBC) into Basal, Luminal, and HER2 subtypes. In most cases, breast tumors have one dominant subtype, representative of a single activated pathway. However, some tumors show a statistically equal representation of more than one subtype, referred to as dual subtype. This study aims to identify and examine dual subtype tumors by BP to understand their biology and possible implications for treatment guidance. METHODS The BP scores of over 15,000 tumor samples from EBC patients were analyzed, and the differences between the highest and the lowest scoring subtypes were calculated. Based upon the distribution of the differences between BP scores, a threshold was determined for each subtype to identify dual versus single subtypes. RESULTS Approximately 97% of samples had one single activated BluePrint molecular subtype, whereas ~ 3% of samples were classified as BP dual subtype. The most frequently occurring dual subtypes were the Luminal-Basal-type and Luminal-HER2-type. Luminal-Basal-type displays a distinct biology from the Luminal single type and Basal single type. Burstein's classification of the single and dual Basal samples showed that the Luminal-Basal-type is mostly classified as 'luminal androgen receptor' and 'mesenchymal' subtypes, supporting molecular evidence of AR activation in the Luminal-Basal-type tumors. Tumors classified as Luminal-HER2-type resemble features of both Luminal-single-type and HER2-single-type. However, patients with dual Luminal-HER2-type have a lower pathological complete response after receiving HER2-targeted therapies in addition to chemotherapy in comparison with patients with a HER2-single-type. CONCLUSION This study demonstrates that BP identifies tumors with two active functional pathways (dual subtype) with specific transcriptional characteristics and highlights the added value of distinguishing BP dual from single subtypes as evidenced by distinct treatment response rates.
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Affiliation(s)
- Midas M Kuilman
- Department of Research and Development, Agendia N.V, Radarweg 60, 1043 NT, Amsterdam, The Netherlands
| | - Architha Ellappalayam
- Department of Research and Development, Agendia N.V, Radarweg 60, 1043 NT, Amsterdam, The Netherlands
| | - Andrei Barcaru
- Department of Research and Development, Agendia N.V, Radarweg 60, 1043 NT, Amsterdam, The Netherlands
| | - Josien C Haan
- Department of Research and Development, Agendia N.V, Radarweg 60, 1043 NT, Amsterdam, The Netherlands
| | - Rajith Bhaskaran
- Department of Research and Development, Agendia N.V, Radarweg 60, 1043 NT, Amsterdam, The Netherlands
| | - Diederik Wehkamp
- Department of Research and Development, Agendia N.V, Radarweg 60, 1043 NT, Amsterdam, The Netherlands
| | - Andrea R Menicucci
- Department of Medical Affairs, Agendia Inc, 22 Morgan, Irvine, CA, 92618, USA
| | - William M Audeh
- Department of Medical Affairs, Agendia Inc, 22 Morgan, Irvine, CA, 92618, USA
| | - Lorenza Mittempergher
- Department of Research and Development, Agendia N.V, Radarweg 60, 1043 NT, Amsterdam, The Netherlands.
| | - Annuska M Glas
- Department of Research and Development, Agendia N.V, Radarweg 60, 1043 NT, Amsterdam, The Netherlands.
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28
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Mathur R, Jha NK, Saini G, Jha SK, Shukla SP, Filipejová Z, Kesari KK, Iqbal D, Nand P, Upadhye VJ, Jha AK, Roychoudhury S, Slama P. Epigenetic factors in breast cancer therapy. Front Genet 2022; 13:886487. [PMID: 36212140 PMCID: PMC9539821 DOI: 10.3389/fgene.2022.886487] [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: 02/28/2022] [Accepted: 07/20/2022] [Indexed: 11/17/2022] Open
Abstract
Epigenetic modifications are inherited differences in cellular phenotypes, such as cell gene expression alterations, that occur during somatic cell divisions (also, in rare circumstances, in germ line transmission), but no alterations to the DNA sequence are involved. Histone alterations, polycomb/trithorax associated proteins, short non-coding or short RNAs, long non—coding RNAs (lncRNAs), & DNA methylation are just a few biological processes involved in epigenetic events. These various modifications are intricately linked. The transcriptional potential of genes is closely conditioned by epigenetic control, which is crucial in normal growth and development. Epigenetic mechanisms transmit genomic adaptation to an environment, resulting in a specific phenotype. The purpose of this systematic review is to glance at the roles of Estrogen signalling, polycomb/trithorax associated proteins, DNA methylation in breast cancer progression, as well as epigenetic mechanisms in breast cancer therapy, with an emphasis on functionality, regulatory factors, therapeutic value, and future challenges.
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Affiliation(s)
- Runjhun Mathur
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India
- Dr. A.P.J Abdul Kalam Technical University, Lucknow, India
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India
- Department of Biotechnology, School of Applied and Life Sciences (SALS), Uttaranchal University, Dehradun, India
- Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali, India
| | - Gaurav Saini
- Department of Civil Engineering, Netaji Subhas University of Technology, Delhi, India
| | - Saurabh Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India
- Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali, India
| | - Sheo Prasad Shukla
- Department of Civil Engineering, Rajkiya Engineering College, Banda, India
| | - Zita Filipejová
- Small Animal Clinic, University of Veterinary Sciences Brno, Brno, Czechia
| | | | - Danish Iqbal
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al Majma'ah, Saudi Arabia
- Health and Basic Sciences Research Center, Majmaah University, Al Majma'ah, Saudi Arabia
| | - Parma Nand
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India
| | - Vijay Jagdish Upadhye
- Center of Research for Development (CR4D), Parul Institute of Applied Sciences (PIAS), Parul University, Vadodara, Gujarat
| | - Abhimanyu Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India
- *Correspondence: Abhimanyu Kumar Jha, ; Shubhadeep Roychoudhury,
| | - Shubhadeep Roychoudhury
- Department of Life Science and Bioinformatics, Assam University, Silchar, India
- *Correspondence: Abhimanyu Kumar Jha, ; Shubhadeep Roychoudhury,
| | - Petr Slama
- Department of Animal Morphology, Physiology, and Genetics, Faculty of AgriSciences, Mendel University in Brno, Brno, Czechia
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Acconcia F. Evaluation of the Sensitivity of Breast Cancer Cell Lines to Cardiac Glycosides Unveils ATP1B3 as a Possible Biomarker for the Personalized Treatment of ERα Expressing Breast Cancers. Int J Mol Sci 2022; 23:ijms231911102. [PMID: 36232400 PMCID: PMC9569938 DOI: 10.3390/ijms231911102] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/17/2022] [Accepted: 09/18/2022] [Indexed: 11/30/2022] Open
Abstract
The molecular classification of breast cancer (BC) dictates pharmacological treatment. Estrogen receptor α (ERα) expressing tumors are treated with 4OH-tamoxifen or fulvestrant, which inhibits the receptor, or with aromatase inhibitors (i.e., anastrozole, letrozole, and exemestane) that reduce the 17β-estradiol (E2) circulating blood levels. Besides such endocrine therapy (ET) drugs, ERα-positive BCs can be treated with epidermal growth factor receptor (EGF-R) inhibitors (i.e., gefitinib, erlotinib, and lapatinib) according to HER2 expression. Notwithstanding these anti-BC drugs, novel personalized approaches for BC treatment are required because prolonged administration of those pharmaceutics determines resistant phenotypes, which result in metastatic BC. We have recently reported that the cardiac glycoside (CG) (i.e., Na/K ATPase inhibitor) ouabain could be repurposed for ERα-positive primary and metastatic BC treatment as it induces ERα degradation and kills BC cells. Here, we evaluated if other CGs could represent additional treatment options for ERα-positive BCs and if the Na/K ATPase could be considered a biomarker for ERα-positive BC treatment. The results indicate that the ATP1B3 Na/K ATPase isoform can educate the choice for the personalized treatment of ERα-positive BC with CGs and that CGs could be more efficacious if they are administered in association with gefitinib.
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Affiliation(s)
- Filippo Acconcia
- Department of Sciences, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146 Rome, Italy
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30
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Musheyev D, Alayev A. Endocrine therapy resistance: what we know and future directions. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:480-496. [PMID: 36071983 PMCID: PMC9446423 DOI: 10.37349/etat.2022.00096] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 05/24/2022] [Indexed: 11/19/2022] Open
Abstract
Endocrine resistance is a major hurdle in the treatment of estrogen receptor (ER)-positive breast cancer. When abnormally regulated, molecular signals responsible for cellular proliferation, as well as ER itself, allow for cellular evasion of ER-dependent treatments. Therefore, pharmacological treatments that target these evasion mechanisms are beneficial for the treatment of endocrine-resistant breast cancers. This review summarizes currently understood molecular signals that contribute to endocrine resistance and their crosstalk that stem from mitogen-activated protein kinase (MAPK), phosphoinositol-3 kinase/protein kinase B (PI3K/AKT), mechanistic target of rapamycin (mTOR), cyclin-dependent kinases 4 and 6 (CDK4/6) and aberrant ER function. Recent clinical trials that target these molecular signals as a treatment strategy for endocrine-resistant breast cancer are also highlighted.
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Affiliation(s)
- David Musheyev
- Alayev Lab, Stern College for Women, Biology Department, Yeshiva University, New York, NY 10174, USA
| | - Anya Alayev
- Alayev Lab, Stern College for Women, Biology Department, Yeshiva University, New York, NY 10174, USA
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31
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Jacobs AT, Martinez Castaneda-Cruz D, Rose MM, Connelly L. Targeted therapy for breast cancer: An overview of drug classes and outcomes. Biochem Pharmacol 2022; 204:115209. [PMID: 35973582 DOI: 10.1016/j.bcp.2022.115209] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/07/2022] [Accepted: 08/09/2022] [Indexed: 12/20/2022]
Abstract
The last 25 years have seen significant growth in new therapeutic options for breast cancer, termed targeted therapies based on their ability to block specific pathways known to drive breast tumor growth and survival. Introduction of these drugs has been made possible through advances in the understanding of breast cancer biology. While the promise of targeted therapy for breast cancer has been clear for some time, the experience of the clinical use of multiple drugs and drug classes allows us to now present a summary and perspective as to the success and impact of this endeavor. Here we will review breast cancer targeted therapeutics in clinical use. We will provide the rationale for their indications and summarize clinical data in patients with different breast cancer subtypes, their impact on breast cancer progression and survival and their major adverse effects. The focus of this review will be on the development that has occurred within classes of targeted therapies and subsequent impact on breast cancer patient outcomes. We will conclude with a perspective on the role of targeted therapy in breast cancer treatment and highlight future areas of development.
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Affiliation(s)
- Aaron T Jacobs
- California University of Science and Medicine, 1501 Violet Street, Colton, CA 92324, United States
| | | | - Mark M Rose
- California University of Science and Medicine, 1501 Violet Street, Colton, CA 92324, United States
| | - Linda Connelly
- California University of Science and Medicine, 1501 Violet Street, Colton, CA 92324, United States.
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32
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Yu J, Mu Q, Fung M, Xu X, Zhu L, Ho RJY. Challenges and opportunities in metastatic breast cancer treatments: Nano-drug combinations delivered preferentially to metastatic cells may enhance therapeutic response. Pharmacol Ther 2022; 236:108108. [PMID: 34999182 PMCID: PMC9256851 DOI: 10.1016/j.pharmthera.2022.108108] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 12/12/2021] [Accepted: 01/03/2022] [Indexed: 02/07/2023]
Abstract
Despite advances in breast cancer treatments and related 5-year survival outcomes, metastatic breast cancer cures remain elusive. The current standard of care includes a combination of surgery, radiation therapy and drug therapy. However, even the most advanced procedures and treatments do not prevent breast cancer recurrence and metastasis. Once metastasis occurs, patient prognosis is poor. Recent elucidation of the spatiotemporal transit of metastatic cancer cells from primary tumor sites to distant sites provide an opportunity to integrate knowledge of drug disposition in our effort to enhance drug localization and exposure in cancer laden tissues . Novel technologies have been developed, but could be further refined to facilitate the distribution of drugs to target cancer cells and tissues. The purpose of this review is to highlight the challenges in metastatic breast cancer treatment and focus on novel drug combination and nanotechnology approaches to overcome the challenges. With improved definition of metastatic tissue target, directed localization and retention of multiple, pharmacologically active drugs to tissues and cells of interest may overcome the limitations in breast cancer treatment that may lead to a cure for breast cancer.
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Affiliation(s)
- Jesse Yu
- Department of Pharmaceutics, University of Washington, Seattle, WA 98195, USA
| | - Qingxin Mu
- Department of Pharmaceutics, University of Washington, Seattle, WA 98195, USA
| | - Millie Fung
- Department of Pharmaceutics, University of Washington, Seattle, WA 98195, USA
| | - Xiaolin Xu
- Department of Pharmaceutics, University of Washington, Seattle, WA 98195, USA
| | - Linxi Zhu
- Department of Pharmaceutics, University of Washington, Seattle, WA 98195, USA
| | - Rodney J Y Ho
- Department of Pharmaceutics, University of Washington, Seattle, WA 98195, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
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33
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Zhou H, Wang L, Liu S, Wang W. The role of phosphoinositide 3-kinases in immune-inflammatory responses: potential therapeutic targets for abdominal aortic aneurysm. Cell Cycle 2022; 21:2339-2364. [PMID: 35792922 DOI: 10.1080/15384101.2022.2094577] [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: 02/08/2023] Open
Abstract
The pathogenesis of abdominal aortic aneurysm (AAA) includes inflammatory responses, matrix metalloproteinases (MMPs) degradation, VSMC apoptosis, oxidative stress, and angiogenesis, among which the inflammatory response plays a key role. At present, surgery is the only curing treatment, and no effective drug can delay AAA progression in clinical practice. Therefore, searching for a signaling pathway related to the immune-inflammatory response is an essential direction for developing drugs targeting AAA. Recent studies have confirmed that the PI3K family plays an important role in many inflammatory diseases and is involved in regulating various cellular functions, especially in the immune-inflammatory response. This review focuses on the role of each isoform of PI3K in each stage of AAA immune-inflammatory response, making available explorations for a deeper understanding of the mechanism of inflammation and immune response during the formation and development of AAA.
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Affiliation(s)
- Haiyang Zhou
- Department of General &vascular Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Lei Wang
- Department of General &vascular Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Shuai Liu
- Department of General &vascular Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Wei Wang
- Department of General &vascular Surgery, Xiangya Hospital, Central South University, Changsha, China
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Kumarasamy V, Nambiar R, Wang J, Rosenheck H, Witkiewicz AK, Knudsen ES. RB loss determines selective resistance and novel vulnerabilities in ER-positive breast cancer models. Oncogene 2022; 41:3524-3538. [PMID: 35676324 PMCID: PMC10680093 DOI: 10.1038/s41388-022-02362-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 05/11/2022] [Accepted: 05/24/2022] [Indexed: 11/09/2022]
Abstract
The management of metastatic estrogen receptor (ER) positive HER2 negative breast cancer (ER+) has improved; however, therapeutic resistance and disease progression emerges in majority of cases. Using unbiased approaches, as expected PI3K and MTOR inhibitors emerge as potent inhibitors to delay proliferation of ER+ models harboring PIK3CA mutations. However, the cytostatic efficacy of these drugs is hindered due to marginal impact on the expression of cyclin D1. Different combination approaches involving the inhibition of ER pathway or cell cycle result in durable growth arrest via RB activation and subsequent inhibition of CDK2 activity. However, cell cycle alterations due to RB loss or ectopic CDK4/cyclin D1 activation yields resistance to these cytostatic combination treatments. To define means to counter resistance to targeted therapies imparted with RB loss; complementary drug screens were performed with RB-deleted isogenic cell lines. In this setting, RB loss renders ER+ breast cancer models more vulnerable to drugs that target DNA replication and mitosis. Pairwise combinations using these classes of drugs defines greater selectivity for RB deficiency. The combination of AURK and WEE1 inhibitors, yields synergistic cell death selectively in RB-deleted ER+ breast cancer cells via apoptosis and yields profound disease control in vivo. Through unbiased efforts the XIAP/CIAP inhibitor birinapant was identified as a novel RB-selective agent. Birinapant further enhances the cytotoxic effect of chemotherapies and targeted therapies used in the treatment of ER+ breast cancer models selectively in the RB-deficient setting. Using organoid culture and xenograft models, we demonstrate the highly selective use of birinapant based combinations for the treatment of RB-deficient tumors. Together, these data illustrate the critical role of RB-pathway in response to many agents used to treat ER+ breast cancer, whilst informing new therapeutic approaches that could be deployed against resistant disease.
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Affiliation(s)
- Vishnu Kumarasamy
- Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Ram Nambiar
- Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Jianxin Wang
- Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Hanna Rosenheck
- Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Agnieszka K Witkiewicz
- Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
| | - Erik S Knudsen
- Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
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Tecalco-Cruz AC, Macías-Silva M, Ramírez-Jarquín JO, Ramírez-Jarquín UN. Decoding the Therapeutic Implications of the ERα Stability and Subcellular Distribution in Breast Cancer. Front Endocrinol (Lausanne) 2022; 13:867448. [PMID: 35498431 PMCID: PMC9044904 DOI: 10.3389/fendo.2022.867448] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 03/03/2022] [Indexed: 01/22/2023] Open
Abstract
Approximately 70% of all breast cancer cases are estrogen receptor-alpha positive (ERα+) and any ERα signaling pathways deregulation is critical for the progression of malignant mammary neoplasia. ERα acts as a transcription factor that promotes the expression of estrogen target genes associated with pro-tumor activity in breast cancer cells. Furthermore, ERα is also part of extranuclear signaling pathways related to endocrine resistance. The regulation of ERα subcellular distribution and protein stability is critical to regulate its functions and, consequently, influence the response to endocrine therapies and progression of this pathology. This minireview highlights studies that have deciphered the molecular mechanisms implicated in controlling ERα stability and nucleo-cytoplasmic transport. These mechanisms offer information about novel biomarkers, therapeutic targets, and promising strategies for breast cancer treatment.
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Affiliation(s)
- Angeles C. Tecalco-Cruz
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México (UACM), Mexico City, Mexico
| | - Marina Macías-Silva
- Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | | | - Uri Nimrod Ramírez-Jarquín
- Neural Signal Transduction, Max Planck Florida Institute for Neuroscience, Jupiter, FL, United States
- Instituto Nacional de Cardiología “Ignacio Chávez”, Mexico City, Mexico
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36
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Moore KM, Cerqueira V, MacLeod KG, Mullen P, Hayward RL, Green S, Harrison DJ, Cameron DA, Langdon SP. Collateral-resistance to estrogen and HER-activated growth is associated with modified AKT, ERα, and cell-cycle signaling in a breast cancer model. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:97-116. [PMID: 35441158 PMCID: PMC7612628 DOI: 10.37349/etat.2022.00074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Aim: A model of progressively endocrine-resistant breast cancer was investigated to identify changes that can occur in signaling pathways after endocrine manipulation. Methods: The MCF7 breast cancer model is sensitive to estrogens and anti-estrogens while variant lines previously derived from wild-type MCF7 are either relatively 17β-estradiol (E2
)-insensitive (LCC1) or fully resistant to estrogen and anti-estrogens (LCC9). Results: In LCC1 and LCC9 cell lines, loss of estrogen sensitivity was accompanied by loss of growth response to transforming growth factor alpha (TGFα), heregulin-beta and pertuzumab. LCC1 and LCC9 cells had enhanced AKT phosphorylation relative to MCF7 which was reflected in downstream activation of phospho-mechanistic target of rapamycin (mTOR), phospho-S6, and phospho-estrogen receptor alpha Ser167 [ERα(Ser167)]. Both AKT2 and AKT3 were phosphorylated in the resistant cell lines, but small interfering RNA (siRNA) knockdown suggested that all three AKT isoforms contributed to growth response. ERα(Ser118) phosphorylation was increased by E2 and TGFα in MCF7, by E2 only in LCC1, but by neither in LCC9 cells. Multiple alterations in E2-mediated cell cycle control were identified in the endocrine-resistant cell lines including increased expression of MYC, cyclin A1, cyclin D1, cyclin-dependent kinase 1 (CDK1), CDK2, and hyperphosphorylated retinoblastoma protein (ppRb), whereas p21 and p27 were reduced. Estrogen modulated expression of these regulators in MCF7 and LCC1 cells but not in LCC9 cells. Seliciclib inhibited CDK2 activation in MCF7 cells but not in resistant variants; in all lines, it reduced ppRb, increased p53 associated responses including p21, p53 up-regulated modulator of apoptosis (PUMA), and p53 apoptosis-inducing protein 1 (p53AIP1), inhibited growth, and produced G2/M block and apoptosis. Conclusions: Multiple changes occur with progression of endocrine resistance in this model with AKT activation contributing to E2 insensitivity and loss of ERα(Ser118) phosphorylation being associated with full resistance. Cell cycle regulation is modified in endocrine-resistant breast cancer cells, and seliciclib is effective in both endocrine-sensitive and resistant diseases.
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Affiliation(s)
- Kate M. Moore
- 1Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, EH4 2XR Edinburgh, UK 2Cancer Research UK Barts Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, EC1M 6BQ London, UK
| | - Vera Cerqueira
- 1Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, EH4 2XR Edinburgh, UK 3West of Scotland Clinical Genetics Service, Queen Elizabeth University Hospital, G51 4TF Glasgow, UK
| | - Kenneth G. MacLeod
- 1Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, EH4 2XR Edinburgh, UK
| | - Peter Mullen
- 4School of Medicine, University of St Andrews, North Haugh, KY16 9TF St Andrews, UK
| | - Richard L. Hayward
- 1Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, EH4 2XR Edinburgh, UK
| | - Simon Green
- 5Cyclacel Ltd, James Lindsay Place, Dundee Technopole, DD1 5JJ Dundee, UK
| | - David J. Harrison
- 4School of Medicine, University of St Andrews, North Haugh, KY16 9TF St Andrews, UK
| | - David A. Cameron
- 1Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, EH4 2XR Edinburgh, UK
| | - Simon P. Langdon
- 1Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, EH4 2XR Edinburgh, UK
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Kawiak A, Kostecka A. Regulation of Bcl-2 Family Proteins in Estrogen Receptor-Positive Breast Cancer and Their Implications in Endocrine Therapy. Cancers (Basel) 2022; 14:279. [PMID: 35053443 PMCID: PMC8773933 DOI: 10.3390/cancers14020279] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/20/2021] [Accepted: 12/29/2021] [Indexed: 12/18/2022] Open
Abstract
Estrogen receptor (ER)-positive breast cancer accounts for around two-thirds of breast cancer occurrences, with endocrine therapy serving as first-line therapy in most cases. Targeting estrogen signaling pathways, which play a central role in regulating ER+ breast cell proliferation and survival, has proven to improve patient outcomes. However, despite the undeniable advantages of endocrine therapy, a subset of breast cancer patients develop acquired or intrinsic resistance to ER-targeting agents, limiting their efficacy. The activation of downstream ER signaling pathways upregulates pro-survival mechanisms that have been shown to influence the response of cells to endocrine therapy. The Bcl-2 family proteins play a central role in cell death regulation and have been shown to contribute to endocrine therapy resistance, supporting the survival of breast cancer cells and enhancing cell death evasion. Due to the overexpression of anti-apoptotic Bcl-2 proteins in ER-positive breast cancer, the role of these proteins as potential targets in hormone-responsive breast cancer is growing in interest. In particular, recent advances in the development of BH3 mimetics have enabled their evaluation in preclinical studies with ER+ breast cancer models, and BH3 mimetics have entered early ER+ breast cancer clinical trials. This review summarizes the molecular mechanisms underlying the regulation of Bcl-2 family proteins in ER+ breast cancer. Furthermore, an overview of recent advances in research regarding the efficacy of BH3 mimetics in ER+ breast cancer has been provided.
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Affiliation(s)
- Anna Kawiak
- Intercollegiate Faculty of Biotechnology, University of Gdansk, Abrahama 58, 80-307 Gdansk, Poland
| | - Anna Kostecka
- Faculty of Pharmacy, Medical University of Gdansk, Hallera 107, 80-416 Gdansk, Poland;
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Muralidharan R. Applied Physiology of Breast Cancer. Breast Cancer 2022. [DOI: 10.1007/978-981-16-4546-4_3] [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]
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Lloyd MR, Wander SA, Hamilton E, Razavi P, Bardia A. Next-generation selective estrogen receptor degraders and other novel endocrine therapies for management of metastatic hormone receptor-positive breast cancer: current and emerging role. Ther Adv Med Oncol 2022; 14:17588359221113694. [PMID: 35923930 PMCID: PMC9340905 DOI: 10.1177/17588359221113694] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 06/28/2022] [Indexed: 11/17/2022] Open
Abstract
Endocrine therapy (ET) is a pivotal strategy to manage early- and advanced-stage estrogen receptor-positive (ER+) breast cancer. In patients with metastatic breast cancer (MBC), progression of disease inevitably occurs due to the presence of acquired or intrinsic resistance mechanisms. ET resistance can be driven by ligand-independent, ER-mediated signaling that promotes tumor proliferation in the absence of hormone, or ER-independent oncogenic signaling that circumvents endocrine regulated transcription pathways. Estrogen receptor 1 (ESR1) mutations induce constitutive ER activity and upregulate ER-dependent gene transcription, provoking resistance to estrogen deprivation and aromatase inhibitor therapy. The role ESR1 mutations play in regulating response to other therapies, such as the selective estrogen receptor degrader (SERD) fulvestrant and the available CDK4/6 inhibitors, is less clear. Novel oral SERDs and other next-generation ETs are in clinical development for ER+ breast cancer as single agents and in combination with established targeted therapies. Recent results from the phase III EMERALD trial demonstrated improved outcomes with the oral SERD elacestrant compared to standard anti-estrogen therapies in ER+ MBC after prior progression on ET, and other agents have shown promise in both the laboratory and early-phase clinical trials. In this review, we will discuss the emerging data related to oral SERDs and other novel ET in managing ER+ breast cancer. As clinical data continue to mature on these next-generation ETs, important questions will emerge related to the optimal sequence of therapeutic options and the genomic and molecular landscape of resistance to these agents.
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Affiliation(s)
- Maxwell R. Lloyd
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Seth A. Wander
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Erika Hamilton
- Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA
| | - Pedram Razavi
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Aditya Bardia
- Massachusetts General Hospital Cancer Center, 10 North Grove Street, Harvard Medical School, Boston, MA 02114-2621, USA
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Acconcia F, Fiocchetti M, Busonero C, Fernandez VS, Montalesi E, Cipolletti M, Pallottini V, Marino M. The extra-nuclear interactome of the estrogen receptors: implications for physiological functions. Mol Cell Endocrinol 2021; 538:111452. [PMID: 34500041 DOI: 10.1016/j.mce.2021.111452] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 08/19/2021] [Accepted: 09/02/2021] [Indexed: 02/07/2023]
Abstract
Over the last decades, a great body of evidence has defined a novel view of the cellular mechanism of action of the steroid hormone 17β-estradiol (E2) through its estrogen receptors (i.e., ERα and ERβ). It is now clear that the E2-activated ERs work both as transcription factors and extra-nuclear plasma membrane-localized receptors. The activation of a plethora of signal transduction cascades follows the E2-dependent engagement of plasma membrane-localized ERs and is required for the coordination of gene expression, which ultimately controls the occurrence of the pleiotropic effects of E2. The definition of the molecular mechanisms by which the ERs locate at the cell surface (i.e., palmitoylation and protein association) determined the quest for understanding the specificity of the extra-nuclear E2 signaling. The use of mice models lacking the plasma membrane ERα localization unveiled that the extra-nuclear E2 signaling is operational in vivo but tissue-specific. However, the underlying molecular details for such ERs signaling diversity in the perspective of the E2 physiological functions in the different cellular contexts are still not understood. Therefore, to gain insights into the tissue specificity of the extra-nuclear E2 signaling to physiological functions, here we reviewed the known ERs extra-nuclear interactors and tried to extrapolate from available databases the ERα and ERβ extra-nuclear interactomes. Based on literature data, it is possible to conclude that by specifically binding to extra-nuclear localized proteins in different sub-cellular compartments, the ERs fine-tune their molecular activities. Moreover, we report that the context-dependent diversity of the ERs-mediated extra-nuclear E2 actions can be ascribed to the great flexibility of the physical structures of ERs and the spatial-temporal organization of the logistics of the cells (i.e., the endocytic compartments). Finally, we provide lists of proteins belonging to the potential ERα and ERβ extra-nuclear interactomes and propose that the systematic experimental definition of the ERs extra-nuclear interactomes in different tissues represents the next step for the research in the ERs field. Such characterization will be fundamental for the identification of novel druggable targets for the innovative treatment of ERs-related diseases.
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Affiliation(s)
- Filippo Acconcia
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy.
| | - Marco Fiocchetti
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Claudia Busonero
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Virginia Solar Fernandez
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Emiliano Montalesi
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Manuela Cipolletti
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Valentina Pallottini
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Maria Marino
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy.
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Zhang HQ, Zhou JM, Zhang SH, Bian L, Xiao JY, Hao XP, Jiang ZF, Wang T. Efficacy and safety of low-dose everolimus combined with endocrine drugs for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1493. [PMID: 34805355 PMCID: PMC8573446 DOI: 10.21037/atm-21-4273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 09/18/2021] [Indexed: 11/09/2022]
Abstract
Background To analyze the efficacy and safety of everolimus 5 mg/day in combination with endocrine drugs in the treatment of hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer using real-world clinical data. Methods Clinical data of hormone receptor (HR)-positive and HER2-negative patients with advanced breast cancer treated with everolimus combined with endocrine drugs in our center between August 2012 and May 2017 were retrospectively analyzed. Curative effect and adverse reactions were evaluated. Results A total of 110 patients were enrolled in this study, and 87.3% received salvage chemotherapy. The median number of salvage treatment lines was 5 (range: 1–19). The median follow-up duration was 12 months (range: 1–56.3 months), the overall response rate (ORR) was 6.4%, the clinical benefit rate (CBR) was 31.8%, the median progression-free survival (mPFS) was 4.0 months (95% CI: 2.9–5.1 months), and the median overall survival (OS) was 17 months (95% CI: 12.1–21.9 months). The mPFS for patients who received ≤2 treatment line was 11.8 months (95% CI: 4.3–19.3 months). Univariate and multivariate analyses suggested that absence of liver metastases, secondary endocrine resistance, and number of metastasis sites <3 were the main factors influencing the benefit of everolimus combined with endocrine therapy. The most common adverse events of grade 3 were: stomatitis (5.5%), non-infectious pneumonia (1.8%), and erythra (1.8%). No grade 4 adverse reactions were observed. Conclusions Our results showed that everolimus (5 mg/day) combined with endocrine therapy was effective and relatively safe for patients with hormone receptor-positive, HER2-negative metastatic breast cancer.
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Affiliation(s)
- Hui-Qiang Zhang
- Department of Breast Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jin-Mei Zhou
- Department of Breast Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Shao-Hua Zhang
- Department of Breast Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Li Bian
- Department of Breast Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jin-Yi Xiao
- Department of Breast Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xiao-Peng Hao
- Department of Breast Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ze-Fei Jiang
- Department of Breast Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Tao Wang
- Department of Breast Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
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42
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Estrogenic hormones receptors in Alzheimer's disease. Mol Biol Rep 2021; 48:7517-7526. [PMID: 34657250 DOI: 10.1007/s11033-021-06792-1] [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] [Received: 07/21/2021] [Accepted: 09/15/2021] [Indexed: 02/06/2023]
Abstract
Estrogens are hormones that play a critical role during development and growth for the adequate functioning of the reproductive system of women, as well as for maintaining bones, metabolism, and cognition. During menopause, the levels of estrogens are decreased, altering their signaling mediated by their intracellular receptors such as estrogen receptor alpha and beta (ERα and ERβ), and G protein-coupled estrogen receptor (GPER). In the brain, the reduction of molecular pathways mediated by estrogenic receptors seems to favor the progression of Alzheimer's disease (AD) in postmenopausal women. In this review, we investigate the participation of estrogen receptors in AD in women during aging.
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43
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Babyshkina N, Dronova T, Erdyneeva D, Gervas P, Cherdyntseva N. Role of TGF-β signaling in the mechanisms of tamoxifen resistance. Cytokine Growth Factor Rev 2021; 62:62-69. [PMID: 34635390 DOI: 10.1016/j.cytogfr.2021.09.005] [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: 07/21/2021] [Revised: 09/18/2021] [Accepted: 09/19/2021] [Indexed: 12/24/2022]
Abstract
The transforming growth factor beta (TGF-β) signaling pathway plays complex role in the regulation of cell proliferation, apoptosis and differentiation in breast cancer. TGF-β activation can lead to multiple cellular responses mediating the drug resistance evolution, including the resistance to antiestrogens. Tamoxifen is the most commonly prescribed antiestrogen that functionally involved in regulation of TGF-β activity. In this review, we focus on the role of TGF-β signaling in the mechanisms of tamoxifen resistance, including its interaction with estrogen receptors alfa (ERα) pathway and breast cancer stem cells (BCSCs). We summarize the current reported data regarding TGF-β signaling components as markers of tamoxifen resistance and review current approaches to overcoming tamoxifen resistance based on studies of TGF-β signaling.
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Affiliation(s)
- Nataliya Babyshkina
- Department of Molecular Oncology and Immunology, Саncеr Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634050, Russian Federation; Siberian State Medical University, Tomsk 634050, Russian Federation.
| | - Tatyana Dronova
- Department of Biology of Tumor Progression, Саncеr Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634050, Russian Federation
| | - Daiana Erdyneeva
- Department of Molecular Oncology and Immunology, Саncеr Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634050, Russian Federation
| | - Polina Gervas
- Department of Molecular Oncology and Immunology, Саncеr Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634050, Russian Federation
| | - Nadejda Cherdyntseva
- Department of Molecular Oncology and Immunology, Саncеr Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634050, Russian Federation
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44
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Mazumder A, Shiao S, Haricharan S. HER2 Activation and Endocrine Treatment Resistance in HER2-negative Breast Cancer. Endocrinology 2021; 162:6329618. [PMID: 34320193 PMCID: PMC8379900 DOI: 10.1210/endocr/bqab153] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Indexed: 11/19/2022]
Abstract
The lethality of estrogen receptor alpha positive (ER+) breast cancer, which is often considered to have better prognosis than other subtypes, is defined by resistance to the standard of care endocrine treatment. Relapse and metastasis are inevitable in almost every patient whose cancer is resistant to endocrine treatment. Therefore, understanding the underlying causes of treatment resistance remains an important biological and clinical focus of research in this area. Growth factor receptor pathway activation, specifically HER2 activation, has been identified as 1 mechanism of endocrine treatment resistance across a range of experimental model systems. However, clinical trials conducted to test whether targeting HER2 benefits patients with endocrine treatment-resistant ER+ breast cancer have consistently and disappointingly shown mixed results. One reason for the failure of these clinical trials could be the complexity of crosstalk between ER, HER2, and other growth factor receptors and the fluidity of HER2 activation in these cells, which makes it challenging to identify stratifiers for this targeted intervention. In the absence of stratifiers that can be assayed at diagnosis to allow prospective tailoring of HER2 inhibition to the right patients, clinical trials will continue to disappoint. To understand stratifiers, it is important that the field invests in key understudied areas of research including characterization of the tumor secretome and receptor activation in response to endocrine treatment, and mapping the ER-HER2 growth factor network in the normal and developing mammary gland. Understanding these mechanisms further is critical to improving outcomes for the hard-to-treat endocrine treatment-resistant ER+ breast cancer cohort.
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Affiliation(s)
- Aloran Mazumder
- Aging and Cancer Immuno-oncology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Stephen Shiao
- Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Svasti Haricharan
- Aging and Cancer Immuno-oncology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
- Correspondence: Svasti Haricharan, PhD, Sanford Burnham Prebys, 10901 N Torrey Pines Rd, La Jolla, CA, USA.
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45
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Everolimus plus aromatase inhibitors as maintenance therapy after first-line chemotherapy: Final results of the phase III randomised MAIN-A (MAINtenance Afinitor) trial. Eur J Cancer 2021; 154:21-29. [PMID: 34225066 DOI: 10.1016/j.ejca.2021.05.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/29/2021] [Accepted: 05/05/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Despite endocrine therapy being the mainstay of treatment for hormone receptor positive (HR+)/HER2- metastatic breast cancer, patients at risk of visceral crisis or doubt for endocrine sensitivity are still offered first-line chemotherapy. Maintenance hormonal therapy is generally offered at the discontinuation of chemotherapy. The MAINtenance Afinitor study is a randomised, phase III trial comparing maintenance everolimus combined with aromatase inhibitors (AIs) versus AI monotherapy in patients with disease control after first-line chemotherapy. METHODS Patients with stable disease, partial response or complete response after first-line chemotherapy were randomised to everolimus plus AIs (exemestane or letrozole or anastrozole) or to AIs alone. Primary aim was progression-free survival (PFS). Secondary aims included response rate, safety and overall survival (OS). RESULTS In total, 110 patients were randomised to everolimus + AIs (n = 52) or to AIs (n = 58). Median PFS was 11.0 months (95% confidence interval [CI] 8.1-13.8) in the everolimus + AI arm and 7.2 months (95% CI 4.7-10.9) in the AI monotherapy arm (hazard ratio [HR] 0.71, 95% CI 0.47-1.06). Objective response rate was 22.4% in everolimus + AI arm and 19.2% in AI monotherapy arm. A higher proportion of disease progression as best response was reported in the AI monotherapy arm (28.8% versus 14.3%). Median OS was 35.7 months (95% CI 26.0-47.8) in the combination arm versus 33.5 (95% CI 26.4-42.7) in the AI alone arm (HR 1.0, 95% CI 0.61-1.62). CONCLUSIONS EVE + AIs did not significantly impact on the outcome of metastatic breast cancer patients deemed suitable for first-line chemotherapy. Also taking into account treatment tolerability, maintenance endocrine therapy remains the standard. TRIAL REGISTRATION EudraCT: 2013-004153-24.
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46
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Punturi NB, Seker S, Devarakonda V, Mazumder A, Kalra R, Chen CH, Li S, Primeau T, Ellis MJ, Kavuri SM, Haricharan S. Mismatch repair deficiency predicts response to HER2 blockade in HER2-negative breast cancer. Nat Commun 2021; 12:2940. [PMID: 34011995 PMCID: PMC8134423 DOI: 10.1038/s41467-021-23271-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 04/22/2021] [Indexed: 01/02/2023] Open
Abstract
Resistance to endocrine treatment occurs in ~30% of ER+ breast cancer patients resulting in ~40,000 deaths/year in the USA. Preclinical studies strongly implicate activation of growth factor receptor, HER2 in endocrine treatment resistance. However, clinical trials of pan-HER inhibitors in ER+/HER2- patients have disappointed, likely due to a lack of predictive biomarkers. Here we demonstrate that loss of mismatch repair activates HER2 after endocrine treatment in ER+/HER2- breast cancer cells by protecting HER2 from protein trafficking. Additionally, HER2 activation is indispensable for endocrine treatment resistance in MutL- cells. Consequently, inhibiting HER2 restores sensitivity to endocrine treatment. Patient data from multiple clinical datasets supports an association between MutL loss, HER2 upregulation, and sensitivity to HER inhibitors in ER+/HER2- patients. These results provide strong rationale for MutL loss as a first-in-class predictive marker of sensitivity to combinatorial treatment with endocrine intervention and HER inhibitors in endocrine treatment-resistant ER+/HER2- breast cancer patients.
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MESH Headings
- Animals
- Breast Neoplasms/drug therapy
- Breast Neoplasms/genetics
- Breast Neoplasms/metabolism
- Cell Line, Tumor
- DNA Mismatch Repair/drug effects
- DNA Mismatch Repair/genetics
- Drug Resistance, Neoplasm/genetics
- Female
- Gene Knockdown Techniques
- Humans
- MCF-7 Cells
- Mice
- Mice, Nude
- Mice, SCID
- MutL Protein Homolog 1/genetics
- MutL Protein Homolog 1/metabolism
- MutL Proteins/genetics
- MutL Proteins/metabolism
- Proteins/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Receptor, ErbB-2/antagonists & inhibitors
- Receptor, ErbB-2/genetics
- Receptor, ErbB-2/metabolism
- Receptors, Estrogen/metabolism
- Signal Transduction
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Nindo B Punturi
- Tumor Microenvironment and Cancer Immunology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Sinem Seker
- Tumor Microenvironment and Cancer Immunology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Vaishnavi Devarakonda
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Aloran Mazumder
- Tumor Microenvironment and Cancer Immunology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Rashi Kalra
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Ching Hui Chen
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Shunqiang Li
- Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Tina Primeau
- Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Matthew J Ellis
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Shyam M Kavuri
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
| | - Svasti Haricharan
- Tumor Microenvironment and Cancer Immunology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
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Cell lineage tracing links ERα loss in Erbb2-positive breast cancers to the arising of a highly aggressive breast cancer subtype. Proc Natl Acad Sci U S A 2021; 118:2100673118. [PMID: 34006643 DOI: 10.1073/pnas.2100673118] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
HER2-positive (HER2+) breast cancers (BrCs) contain approximately equal numbers of ERα+HER2+ and ERα-HER2+ cases. An enduring obstacle is the unclear cell lineage-related characteristics of these BrCs. Although ERα+HER2+ BrCs could lose ERα to become ERα-HER2+ BrCs, direct evidence is missing. To investigate ERα dependencies and their implications during BrC growth and metastasis, we generated ERαCreRFP-T mice that produce an RFP-marked ERα+ mammary gland epithelial cell (MGEC) lineage. RCAS virus-mediated expression of Erbb2, a rodent Her2 homolog, first produced comparable numbers of ERα+RFP+Erbb2+ and ERα-RFP-Erbb2+ MGECs. Early hyperplasia developed mostly from ERα+RFP+Erbb2+ cells and ERα-RFP-Erbb2+ cells in these lesions were rare. The subsequently developed ductal carcinomas in situ had 64% slow-proliferating ERα+RFP+Erbb2+ cells, 15% fast-proliferating ERα-RFP+Erbb2+ cells derived from ERα+RFP+Erbb2+ cells, and 20% fast-proliferating ERα-RFP-Erbb2+ cells. The advanced tumors had mostly ERα-RFP+Erbb2+ and ERα-RFP-Erbb2+ cells and only a very small population of ERα+RFP+Erbb2+ cells. In ERα-RFP+Erbb2+ cells, GATA3 and FoxA1 decreased expression and ERα promoter regions became methylated, consistent with the loss of ERα expression. Lung metastases consisted of mostly ERα-RFP+Erbb2+ cells, a few ERα-RFP-Erbb2+ cells, and no ERα+RFP+Erbb2+ cells. The high metastatic capacity of ERα-RFP+Erbb2+ cells was associated with ERK1/2 activation. These results show that the slow-proliferating, nonmetastatic ERα+RFP+Erbb2+ cells progressively lose ERα during tumorigenesis to become fast-proliferating, highly metastatic ERα-RFP+Erbb2+ cells. The ERα-Erbb2+ BrCs with an ERα+ origin are more aggressive than those ERα-Erbb2+ BrCs with an ERα- origin, and thus, they should be distinguished and treated differently in the future.
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48
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Vernieri C, Nichetti F, Lalli L, Moscetti L, Giorgi CA, Griguolo G, Marra A, Randon G, Rea CG, Ligorio F, Scagnoli S, De Angelis C, Molinelli C, Fabbri A, Ferraro E, Trapani D, Milani A, Agostinetto E, Bernocchi O, Catania G, Vantaggiato A, Palleschi M, Moretti A, Basile D, Cinausero M, Ajazi A, Castagnoli L, Lo Vullo S, Gerratana L, Puglisi F, La Verde N, Arpino G, Rocca A, Ciccarese M, Pedersini R, Fabi A, Generali D, Losurdo A, Montemurro F, Curigliano G, Del Mastro L, Michelotti A, Cortesi E, Guarneri V, Pruneri G, Mariani L, de Braud F. Impact of Baseline and On-Treatment Glycemia on Everolimus-Exemestane Efficacy in Patients with Hormone Receptor-Positive Advanced Breast Cancer (EVERMET). Clin Cancer Res 2021; 27:3443-3455. [PMID: 33785482 DOI: 10.1158/1078-0432.ccr-20-4928] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/24/2021] [Accepted: 03/26/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE The mTOR complex C1 (mTORC1) inhibitor everolimus in combination with the aromatase inhibitor exemestane is an effective treatment for patients with hormone receptor-positive (HR+), HER2-negative (HER2-), advanced breast cancer (HR+/HER2- aBC). However, everolimus can cause hyperglycemia and hyperinsulinemia, which could reactivate the PI3K/protein kinase B (AKT)/mTORC1 pathway and induce tumor resistance to everolimus. EXPERIMENTAL DESIGN We conducted a multicenter, retrospective, Italian study to investigate the impact of baseline and on-treatment (i.e., during first 3 months of therapy) blood glucose levels on progression-free survival (PFS) in patients with HR+/HER2- aBC treated with everolimus-exemestane. RESULTS We evaluated 809 patients with HR+/HER2- aBC treated with everolimus-exemestane as any line of therapy for advanced disease. When evaluated as dichotomous variables, baseline and on-treatment glycemia were not significantly associated with PFS. However, when blood glucose concentration was evaluated as a continuous variable, a multivariable model accounting for clinically relevant patient- and tumor-related variables revealed that both baseline and on-treatment glycemia are associated with PFS, and this association is largely attributable to their interaction. In particular, patients who are normoglycemic at baseline and experience on-treatment diabetes have lower PFS compared with patients who are already hyperglycemic at baseline and experience diabetes during everolimus-exemestane therapy (median PFS, 6.34 vs. 10.32 months; HR, 1.76; 95% confidence interval, 1.15-2.69; P = 0.008). CONCLUSIONS The impact of on-treatment glycemia on the efficacy of everolimus-exemestane therapy in patients with HR+/HER2- aBC depends on baseline glycemia. This study lays the foundations for investigating novel therapeutic approaches to target the glucose/insulin axis in combination with PI3K/AKT/mTORC1 inhibitors in patients with HR+/HER2- aBC.
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Affiliation(s)
- Claudio Vernieri
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. .,IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy
| | - Federico Nichetti
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Luca Lalli
- Unit of Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Luca Moscetti
- Division of Medical Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | | | - Gaia Griguolo
- Medical Oncology 2, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.,Department of Surgery, Oncology and Gastroenterology, University of Padova, Padua, Italy
| | - Antonio Marra
- Division of Early Drug Development for Innovative Therapies, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Giovanni Randon
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Carmen G Rea
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Francesca Ligorio
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Simone Scagnoli
- Department of Medico-Surgical Sciences and Translational Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Claudia De Angelis
- UO Oncologia Medica 2, Ospedale S. Chiara, Dipartimento di Oncologia, Dei Trapianti e Delle Nuove Tecnologie, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
| | - Chiara Molinelli
- IRCCS Ospedale Policlinico San Martino, U.O.S.D. Breast Unit, Genova, Italy
| | - Agnese Fabbri
- Medical Oncology Unit, Belcolle Hospital, Viterbo, Italy
| | - Emanuela Ferraro
- Division of Early Drug Development for Innovative Therapies, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Dario Trapani
- Division of Early Drug Development for Innovative Therapies, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Andrea Milani
- Multidisciplinary Oncology Outpatient Clinic, Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy
| | - Elisa Agostinetto
- Medical Oncology and Hematology Unit, Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy
| | - Ottavia Bernocchi
- Department of Medical, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - Giovanna Catania
- Division of Medical Oncology, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | | | - Michela Palleschi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST, Meldola, Italy
| | - Anna Moretti
- Department of Oncology, ASST Fatebenefratelli Sacco - PO Fatebenefratelli, Milan, Italy
| | - Debora Basile
- Department of Medical Oncology, IRCCS Centro di Riferimento Oncologico di Aviano (CRO), Aviano, Italy
| | - Marika Cinausero
- Department of Oncology, ASUFC University Hospital of Udine, Udine, Italy
| | - Arta Ajazi
- IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy
| | - Lorenzo Castagnoli
- Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Salvatore Lo Vullo
- Unit of Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Lorenzo Gerratana
- Department of Medical Oncology, IRCCS Centro di Riferimento Oncologico di Aviano (CRO), Aviano, Italy.,Department of Medicine, University of Udine, Udine, Italy
| | - Fabio Puglisi
- Department of Medical Oncology, IRCCS Centro di Riferimento Oncologico di Aviano (CRO), Aviano, Italy.,Department of Medicine, University of Udine, Udine, Italy
| | - Nicla La Verde
- Department of Oncology, ASST Fatebenefratelli Sacco - PO Luigi Sacco, Milan, Italy
| | - Grazia Arpino
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Andrea Rocca
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST, Meldola, Italy
| | | | - Rebecca Pedersini
- Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, Medical Oncology, University of Brescia at ASST Spedali Civili, Brescia, Italy
| | - Alessandra Fabi
- Division of Medical Oncology, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Daniele Generali
- Department of Medical, Surgery and Health Sciences, University of Trieste, Trieste, Italy.,Breast Cancer Unit & Translational Research Unit, ASST Cremona, Cremona, Italy
| | - Agnese Losurdo
- Medical Oncology and Hematology Unit, Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy
| | - Filippo Montemurro
- Multidisciplinary Oncology Outpatient Clinic, Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy
| | - Giuseppe Curigliano
- Division of Early Drug Development for Innovative Therapies, IEO, European Institute of Oncology IRCCS, Milan, Italy.,Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Lucia Del Mastro
- IRCCS Ospedale Policlinico San Martino, U.O.S.D. Breast Unit, Genova, Italy.,Dipartimento di Medicina Interna e Specialità Mediche (DiMI), School of Medicine, University of Genova, Genova, Italy
| | - Andrea Michelotti
- UO Oncologia Medica 2, Ospedale S. Chiara, Dipartimento di Oncologia, Dei Trapianti e Delle Nuove Tecnologie, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
| | - Enrico Cortesi
- Department of Medico-Surgical Sciences and Translational Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Valentina Guarneri
- Medical Oncology 2, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.,Department of Surgery, Oncology and Gastroenterology, University of Padova, Padua, Italy
| | - Giancarlo Pruneri
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.,Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Luigi Mariani
- Unit of Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo de Braud
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.,Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
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49
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Im YH, Karabulut B, Lee KS, Park BW, Adhav A, Cinkir HY, Abdel-Razeq H, Chang YC, Aksoy S, Im SA, Jeong J, Chae Y, Bowles J, Slimane K, Xue H, Kim SB. Safety and efficacy of everolimus (EVE) plus exemestane (EXE) in postmenopausal women with locally advanced or metastatic breast cancer: final results from EVEREXES. Breast Cancer Res Treat 2021; 188:77-89. [PMID: 33728524 DOI: 10.1007/s10549-021-06173-z] [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: 12/28/2020] [Accepted: 03/03/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND This study was conducted to collect clinical safety, tolerability, and efficacy data with the use of everolimus (EVE) combined with exemestane (EXE) in patients with advanced breast cancer (ABC). METHODS The EVEREXES trial initiated in 2012, provided early access to the first dual blockade treatment with EVE + EXE in patients with HR+, HER2 - ABC in Asia and other emerging growth countries. Postmenopausal women with HR+, HER2 - ABC who had documented recurrence or progression, following a nonsteroidal aromatase inhibitor therapy, were treated with EVE (10 mg/day) + EXE (25 mg/day) orally. RESULTS A total of 235 patients received ≥ 1 dose of study medication. At the end of the study, all patients ceased the treatment. Disease progression (66.0%) was the primary reason of discontinuation. The most common AEs (≥ 20%) were stomatitis, decreased appetite, hyperglycemia, rash, aspartate aminotransferase increased, anemia, alanine aminotransferase increased, cough, and fatigue. No new safety concerns were identified in the current study. Median progression-free survival (PFS) in the Asian subset was similar to that of the overall population (9.3 months in both groups). Confirmed overall response rate (ORR) was achieved for 19.6% of the patients. Efficacy of EVE + EXE across subgroups (prior CT, line of treatment, and presence of visceral metastases) was maintained. CONCLUSION The safety and efficacy results from EVEREXES trial are consistent to data previously reported in BOLERO-2. These results support that EVE + EXE could be a viable treatment option for the postmenopausal women with HR+, HER2 - ABC in Asian region.
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Affiliation(s)
- Young-Hyuck Im
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
| | - Bulent Karabulut
- Department of Medical Oncology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Keun Seok Lee
- Center for Breast Cancer, National Cancer Center, Gyeonggi do, Korea
| | - Byeong-Woo Park
- Department of Surgery, Yonsei University Health System, Severance Hospital, Seoul, Korea
| | - Aditya Adhav
- Department of Surgical Oncology, HCG Manavata Cancer Centre, Nashik, India
| | - Havva Yesil Cinkir
- Department of Medical Oncology, Gaziantep University Medical Faculty, Gaziantep, Turkey
| | | | | | - Sercan Aksoy
- Hacettepe University Medical Faculty, Ankara, Turkey
| | - Seock-Ah Im
- Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Joon Jeong
- Department of Surgery, Gangnam Severance Hospital Yonsei University Health System, Seoul, Korea
| | - Yeesoo Chae
- Kyungpook National University Hospital, Daegu, Korea
| | | | | | - Hongling Xue
- Novartis Asia Pacific Pharmaceuticals Pte Ltd, Singapore, Singapore
| | - Sung-Bae Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Adjuvant endocrine therapy in HER2-positive breast cancer patients: systematic review and meta-analysis. ESMO Open 2021; 6:100088. [PMID: 33735801 PMCID: PMC7988286 DOI: 10.1016/j.esmoop.2021.100088] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 02/13/2021] [Indexed: 01/22/2023] Open
Abstract
Background Approximately 50% of human epidermal growth factor receptor 2 (HER2)-positive breast cancer lesions express hormone receptors. These tumors present a unique therapeutic challenge, and the optimal endocrine therapeutic approach remains controversial. We aimed to study the optimal adjuvant endocrine therapy in this setting, to better establish the basis for clinical recommendations in HER2-positive disease. Methods We conducted a literature search up to May 2020, in which we identified randomized controlled trials (RCTs) that investigated the efficacy of various adjuvant hormonal therapies among premenopausal and postmenopausal patients with hormone receptor (HR)-positive, HER2-positive early breast cancer. Disease-free survival (DFS) was calculated with the random effect model and hazard ratios (HRs) with 95% confidence intervals (CI). Results Six RCTs (N = 5390 patients) were included in the final analysis. There was no significant difference in DFS between adjuvant treatment with aromatase inhibitors and tamoxifen (HR 0.99, 95% CI 0.68-1.44, P = 0.96). Furthermore, after omitting the ALTTO trial, as it did not randomize patients to hormonal therapy, no significant difference was observed between the two protocols (HR 1.06, 95% CI 0.65-1.73, P = 0.81). Conclusion Our study demonstrates similar DFS with tamoxifen and aromatase inhibitors as adjuvant endocrine treatment in HER2-positive HR-positive early-stage breast cancer patients. Future larger prospective studies focusing on the various contemporary endocrine regimens are warranted to validate our findings.
Optimal adjuvant endocrine therapy for early-stage breast cancer with co-expression of HER2 and hr is unclear. Our analysis demonstrated no difference in disease-free survival between selected endocrine regimens among these patients. Study strength includes longer follow-up, premenopausal patients and current HER2 regimens and combinations.
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