Activity of Estrogen Receptor β Agonists in Therapy-Resistant Estrogen Receptor-Positive Breast Cancer.

Autor:	Datta J; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States., Willingham N; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States., Manouchehri JM; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States., Schnell P; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States.; Stefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, United States., Sheth M; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States., David JJ; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States., Kassem M; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States.; Stefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, United States., Wilson TA; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States.; Medicinal Chemistry Shared Resource, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States., Radomska HS; Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, United States., Coss CC; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States.; Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, United States.; Drug Development Institute, The Ohio State University, Columbus, OH, United States., Bennett CE; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States.; Medicinal Chemistry Shared Resource, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States.; Drug Development Institute, The Ohio State University, Columbus, OH, United States., Ganju RK; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States., Sardesai SD; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States.; Stefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, United States., Lustberg M; Yale Cancer Center, Yale School of Medicine, New Haven, CT, United States., Ramaswamy B; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States.; Stefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, United States., Stover DG; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States.; Stefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, United States., Cherian MA; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States.; Stefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in oncology [Front Oncol] 2022 Apr 25; Vol. 12, pp. 857590. Date of Electronic Publication: 2022 Apr 25 (Print Publication: 2022).
DOI:	10.3389/fonc.2022.857590
Abstrakt:	Background: Among 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. Methods: We 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. Results: In 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. Conclusion: Our 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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Datta, Willingham, Manouchehri, Schnell, Sheth, David, Kassem, Wilson, Radomska, Coss, Bennett, Ganju, Sardesai, Lustberg, Ramaswamy, Stover and Cherian.)
Databáze:	MEDLINE
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