Abstract P6-11-15: Pre-clinical investigation of estrogen receptor β agonists for the treatment of breast cancer

Abstract

Abstract Breast Cancer is the primary cause of cancer-associated mortality worldwide, and in United States alone, more than 250,000 women are diagnosed every year. Current breast cancer treatment strategies focus on Estrogen Receptor α signaling, given that the majority of cases diagnosed are ERα positive. These treatment strategies include endocrine therapies; such as anti-estrogens or aromatase inhibitors. Although, endocrine therapy has been demonstrated to be successful and effective, therapy resistance commonly arises and results in relapse. While current endocrine therapies focus on ERα signaling, emerging studies highlight the importance of Estrogen Receptor β.Unlike ERα, ERβ has been shown to have tumor-suppressive function in various cancers, including breast cancer. Recent studies have identified, synthesized, and tested the clinical safety of ERβ-selective agonists. The objective of this study was to investigate the utility of using ERβ agonists in the treatment of breast cancer. To investigate the utility of ERβ agonists in the treatment of breast cancer, we used in-vitro and in-vivo pre-clinical models systems. Our results demonstrated that treatment with ERβ agonists, S-Equol and LY500307, was able to inhibit the short-term and long-term growth of both endocrine therapy sensitive and resistant breast cancer cells. Progression through the cell cycle, cell migration and cell invasion was also abrogated upon treatment. In-vivo, our syngeneic tumor mouse model demonstrates a decline in tumor growth rate after treating with a combination of letrozole and ERβ agonist. Gene expression array analysis reveal that treatment with ERβ agonist elicits changes in key signaling molecules involved in cell death and cell cycle pathways. In Letrozole resistant cells, Letrozole treatment had not effect on gene expression, while LY500307 treatment resulted in the modulation of 780 genes. Interestingly, combining Letrozole with LY500307 resulted in the modulation of 966 genes, of which 417 were unique to the combination treatment. Our studies suggest that activation of ERβ signaling is a valuable strategy in the treatment of breast cancer, even in cases which have developed resistance to current endocrine therapies. Citation Format: Samayoa C, Krishnegowda NK, Vadlamudi RK, Tekmal RR. Pre-clinical investigation of estrogen receptor β agonists for the treatment of breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-15.