Abstract 3734: Estrogen receptor β agonists suppress the growth and progression of mammary tumors in immune-competent mouse models

Background: Despite medical advances in early detection and treatment, breast cancer still has a relatively high mortality rate in women due to recurrence and metastasis. Many human cancers are able to suppress the activity of the immune system. With the emerging importance of the immune system in tumor surveillance, the need to employ immunocompetent in vivo models to study breast cancer progression is evident. Syngeneic tumor mouse models are a useful tool to study drug development and therapeutic utility of novel drugs. Emerging evidence suggest that Estrogen receptor (ER) β functions as a tumor suppressor in many cancers including breast cancer. Therefore, targeting ERβ with selective agonists may provide therapeutic benefit in the treatment of breast cancer. Herein, we examined the therapeutic efficacy of ERβ agonists on the growth of syngeneic mouse mammary tumors. Experimental design: To test the effects of ERβ agonists on growth, we carried out cell proliferation, invasion and migration, and clonogenic assays in all three-mouse mammary tumor models with different genetic background. Cell cycle was analyzed using FACS analysis. D2A1 (BALB/c) and MM51 (FVB) syngeneic models and ex-vivo culture of E0771 (C57/B6) cells were used to evaluate the antitumor effects of ERβ agonists. Results: First, we assessed the effects of ERβ agonists on cell proliferation of these three mouse mammary tumor cells. Cells were treated with different concentrations of LY500307 (100nM-10µM) and S-Equol (1µM-100µM) for 72 and 96 hrs. D2A1 cells and E0771 cells showed IC 50 of 2.5µM for LY500307 and 50 µM for S-Equol and MM51 cells had an IC 50 of 2 µM for LY500307 and 40 µM for S-Equol. Our results also showed that ERβ agonists reduce the colony formation ability of D2A1 and MM51 cells. In D2A1 and MM51 cells, LY500307 treatment decreased colonies by 32% and 50%, and S-Equol reduced colonies to 18% and 40% as compared to control respectively. Cell cycle analysis showed that LY500307 and S-equol treatment in D2A1 and E0771 cells resulted in a significant accumulation of cells in S phase. Further, we analyzed the therapeutic efficacy of LY500307 in two syngeneic mouse tumor models from D2A1 and MM51 cells. Our results demonstrated that LY500307 inhibited the tumor growth and the effect was more pronounce in combination with aromatase inhibitor letrozole. Further, using ex-vivo model of tumor explants from E0771 cells, we showed that ERβ agonists inhibited the mammary tumor growth. Conclusions: Our results suggested that ERβ agonists have potential to prevent the progression mammary tumors in immunocompetent hosts. Citation Format: Kumaraguruparan Ramasamy, Cathy Samayoa, Naveen K. Krishnegowda, Shaorong Chen, Ratna K. Vadlamudi, Rajeshwar R. Tekmal. Estrogen receptor β agonists suppress the growth and progression of mammary tumors in immune-competent mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3734.