Activity of Estrogen Receptor β Agonists in Therapy-Resistant Estrogen Receptor-Positive Breast Cancer
BackgroundAmong women, breast cancer is the leading cause of cancer-related death worldwide. Estrogen receptor α-positive (ERα+) breast cancer accounts for 70% of all breast cancer subtypes. Although ERα+ breast cancer initially responds to estrogen deprivation or blockade, the emergence of resistan...
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Frontiers Media S.A.
2022-04-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.857590/full |
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| author | Jharna Datta Natalie Willingham Jasmine M. Manouchehri Patrick Schnell Patrick Schnell Mirisha Sheth Joel J. David Mahmoud Kassem Mahmoud Kassem Tyler A. Wilson Tyler A. Wilson Hanna S. Radomska Christopher C. Coss Christopher C. Coss Christopher C. Coss Chad E. Bennett Chad E. Bennett Chad E. Bennett Ramesh K. Ganju Sagar D. Sardesai Sagar D. Sardesai Maryam Lustberg Bhuvaneswari Ramaswamy Bhuvaneswari Ramaswamy Daniel G. Stover Daniel G. Stover Mathew A. Cherian Mathew A. Cherian |
| author_facet | Jharna Datta Natalie Willingham Jasmine M. Manouchehri Patrick Schnell Patrick Schnell Mirisha Sheth Joel J. David Mahmoud Kassem Mahmoud Kassem Tyler A. Wilson Tyler A. Wilson Hanna S. Radomska Christopher C. Coss Christopher C. Coss Christopher C. Coss Chad E. Bennett Chad E. Bennett Chad E. Bennett Ramesh K. Ganju Sagar D. Sardesai Sagar D. Sardesai Maryam Lustberg Bhuvaneswari Ramaswamy Bhuvaneswari Ramaswamy Daniel G. Stover Daniel G. Stover Mathew A. Cherian Mathew A. Cherian |
| author_sort | Jharna Datta |
| collection | DOAJ |
| description | BackgroundAmong women, breast cancer is the leading cause of cancer-related death worldwide. Estrogen receptor α-positive (ERα+) breast cancer accounts for 70% of all breast cancer subtypes. Although ERα+ breast cancer initially responds to estrogen deprivation or blockade, the emergence of resistance compels the use of more aggressive therapies. While ERα is a driver in ERα+ breast cancer, ERβ plays an inhibitory role in several different cancer types. To date, the lack of highly selective ERβ agonists without ERα activity has limited the exploration of ERβ activation as a strategy for ERα+ breast cancer.MethodsWe measured the expression levels of ESR1 and ESR2 genes in immortalized mammary epithelial cells and different breast cancer cell lines. The viability of ERα+ breast cancer cell lines upon treatments with specific ERβ agonists, including OSU-ERb-12 and LY500307, was assessed. The specificity of the ERβ agonists, OSU-ERb-12 and LY500307, was confirmed by reporter assays. The effects of ERβ agonists on cell proliferation, cell cycle, apoptosis, colony formation, cell migration, and expression of tumor suppressor proteins were analyzed. The expression of ESR2 and genes containing ERE-AP1 composite response elements was examined in ERα+ human breast cancer samples to determine the correlation between ESR2 expression and overall survival and that of putative ESR2-regulated genes.ResultsIn this study, we demonstrate the efficacy of highly selective ERβ agonists in ERα+ breast cancer cell lines and drug-resistant derivatives. ERβ agonists blocked cell proliferation, migration, and colony formation and induced apoptosis and S and/or G2/M cell-cycle arrest of ERα+ breast cancer cell lines. Also, increases in the expression of the key tumor suppressors FOXO1 and FOXO3a were noted. Importantly, the strong synergy between ERβ agonists and ERα antagonists suggested that the efficacy of ERβ agonists is maximized by combination with ERα blockade. Lastly, ESR2 (ERβ gene) expression was negatively correlated with ESR1 (ERα gene) and CCND1 RNA expression in human metastatic ERα+/HER2- breast cancer samples.ConclusionOur results demonstrate that highly selective ERβ agonists attenuate the viability of ERα+ breast cancer cell lines in vitro and suggest that this therapeutic strategy merits further evaluation for ERα+ breast cancer. |
| first_indexed | 2024-12-12T19:34:04Z |
| format | Article |
| id | doaj.art-432a0e095a4c45e2800716a4915a5e12 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-12T19:34:04Z |
| publishDate | 2022-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-432a0e095a4c45e2800716a4915a5e122022-12-22T00:14:22ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-04-011210.3389/fonc.2022.857590857590Activity of Estrogen Receptor β Agonists in Therapy-Resistant Estrogen Receptor-Positive Breast CancerJharna Datta0Natalie Willingham1Jasmine M. Manouchehri2Patrick Schnell3Patrick Schnell4Mirisha Sheth5Joel J. David6Mahmoud Kassem7Mahmoud Kassem8Tyler A. Wilson9Tyler A. Wilson10Hanna S. Radomska11Christopher C. Coss12Christopher C. Coss13Christopher C. Coss14Chad E. Bennett15Chad E. Bennett16Chad E. Bennett17Ramesh K. Ganju18Sagar D. Sardesai19Sagar D. Sardesai20Maryam Lustberg21Bhuvaneswari Ramaswamy22Bhuvaneswari Ramaswamy23Daniel G. Stover24Daniel G. Stover25Mathew A. Cherian26Mathew A. Cherian27Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United StatesComprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United StatesComprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United StatesComprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United StatesStefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, United StatesComprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United StatesComprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United StatesComprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United StatesStefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, United StatesComprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United StatesMedicinal Chemistry Shared Resource, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United StatesDivision of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, United StatesComprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United StatesDivision of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, United StatesDrug Development Institute, The Ohio State University, Columbus, OH, United StatesComprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United StatesMedicinal Chemistry Shared Resource, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United StatesDrug Development Institute, The Ohio State University, Columbus, OH, United StatesComprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United StatesComprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United StatesStefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, United StatesYale Cancer Center, Yale School of Medicine, New Haven, CT, United StatesComprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United StatesStefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, United StatesComprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United StatesStefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, United StatesComprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United StatesStefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, United StatesBackgroundAmong women, breast cancer is the leading cause of cancer-related death worldwide. Estrogen receptor α-positive (ERα+) breast cancer accounts for 70% of all breast cancer subtypes. Although ERα+ breast cancer initially responds to estrogen deprivation or blockade, the emergence of resistance compels the use of more aggressive therapies. While ERα is a driver in ERα+ breast cancer, ERβ plays an inhibitory role in several different cancer types. To date, the lack of highly selective ERβ agonists without ERα activity has limited the exploration of ERβ activation as a strategy for ERα+ breast cancer.MethodsWe measured the expression levels of ESR1 and ESR2 genes in immortalized mammary epithelial cells and different breast cancer cell lines. The viability of ERα+ breast cancer cell lines upon treatments with specific ERβ agonists, including OSU-ERb-12 and LY500307, was assessed. The specificity of the ERβ agonists, OSU-ERb-12 and LY500307, was confirmed by reporter assays. The effects of ERβ agonists on cell proliferation, cell cycle, apoptosis, colony formation, cell migration, and expression of tumor suppressor proteins were analyzed. The expression of ESR2 and genes containing ERE-AP1 composite response elements was examined in ERα+ human breast cancer samples to determine the correlation between ESR2 expression and overall survival and that of putative ESR2-regulated genes.ResultsIn this study, we demonstrate the efficacy of highly selective ERβ agonists in ERα+ breast cancer cell lines and drug-resistant derivatives. ERβ agonists blocked cell proliferation, migration, and colony formation and induced apoptosis and S and/or G2/M cell-cycle arrest of ERα+ breast cancer cell lines. Also, increases in the expression of the key tumor suppressors FOXO1 and FOXO3a were noted. Importantly, the strong synergy between ERβ agonists and ERα antagonists suggested that the efficacy of ERβ agonists is maximized by combination with ERα blockade. Lastly, ESR2 (ERβ gene) expression was negatively correlated with ESR1 (ERα gene) and CCND1 RNA expression in human metastatic ERα+/HER2- breast cancer samples.ConclusionOur results demonstrate that highly selective ERβ agonists attenuate the viability of ERα+ breast cancer cell lines in vitro and suggest that this therapeutic strategy merits further evaluation for ERα+ breast cancer.https://www.frontiersin.org/articles/10.3389/fonc.2022.857590/fullERαERβER+ breast cancerOSU-ERb-12LY500307 |
| spellingShingle | Jharna Datta Natalie Willingham Jasmine M. Manouchehri Patrick Schnell Patrick Schnell Mirisha Sheth Joel J. David Mahmoud Kassem Mahmoud Kassem Tyler A. Wilson Tyler A. Wilson Hanna S. Radomska Christopher C. Coss Christopher C. Coss Christopher C. Coss Chad E. Bennett Chad E. Bennett Chad E. Bennett Ramesh K. Ganju Sagar D. Sardesai Sagar D. Sardesai Maryam Lustberg Bhuvaneswari Ramaswamy Bhuvaneswari Ramaswamy Daniel G. Stover Daniel G. Stover Mathew A. Cherian Mathew A. Cherian Activity of Estrogen Receptor β Agonists in Therapy-Resistant Estrogen Receptor-Positive Breast Cancer Frontiers in Oncology ERα ERβ ER+ breast cancer OSU-ERb-12 LY500307 |
| title | Activity of Estrogen Receptor β Agonists in Therapy-Resistant Estrogen Receptor-Positive Breast Cancer |
| title_full | Activity of Estrogen Receptor β Agonists in Therapy-Resistant Estrogen Receptor-Positive Breast Cancer |
| title_fullStr | Activity of Estrogen Receptor β Agonists in Therapy-Resistant Estrogen Receptor-Positive Breast Cancer |
| title_full_unstemmed | Activity of Estrogen Receptor β Agonists in Therapy-Resistant Estrogen Receptor-Positive Breast Cancer |
| title_short | Activity of Estrogen Receptor β Agonists in Therapy-Resistant Estrogen Receptor-Positive Breast Cancer |
| title_sort | activity of estrogen receptor β agonists in therapy resistant estrogen receptor positive breast cancer |
| topic | ERα ERβ ER+ breast cancer OSU-ERb-12 LY500307 |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.857590/full |
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