Abstract P1-04-01: Estrogen receptor β agonists inhibits syngeneic mammary tumor growth through cell-cycle arrest by modulating cell-cycle regulators

Abstract

Abstract Breast Cancer is the main cause of cancer-associated mortality in women worldwide. The estrogen receptors (ER's) play an important role in normal mammary gland development, as well as in breast cancer. Estrogen Receptor α is expressed in 70% of breast cancers, where it contributes to increased cell proliferation and decreased cell death. Endocrine therapies such as anti-estrogens and aromatase inhibitors target ERα signaling and improve outcomes of these patients. Syngeneic, immunocompetent mouse models are essential for elucidating the mechanisms and for evaluating novel strategies for the treatment of breast cancer. In contrast to the tumor-inducing role of ERα, ERβ has been shown to have tumor suppressive activities in various cancer, including the breast cancer. Compounds that selectively activate ERβ hold promise because they could potentially avoid the unwanted effects of ERα activation, while exploiting the tumor-suppressive function of ERβ. In the present study, we assessed the antitumor effects of ERβ agonists using three different syngeneic mouse models; D2A1 (BALB/c) and MM51 (FVB) syngeneic models and ex-vivo culture of highly metastatic cell line E0771 (C57/B6). Effect on in vitro cancer cell growth was evaluated by cell proliferation and clonogenic assays. Cell cycle distribution was analysed by flow cytometry. Our results demonstrate that ERβ agonists LY500307 and S-Equol not only inhibited the growth of all three mouse mammary tumor cell lines, but also reduced the colony formation ability. ERβ agonists also induced the cell-cycle arrest in time and dose-dependent manner. In mechanistic studies, ERβ agonists LY500307 and S-Equol, modulated the protein levels of cyclin-dependent kinases (CDKs) (4, 6, and 2), cyclins (D1 and E), in a differential manner in these three cell lines. Our in vivo studies of D2A1 and MM51 cells demonstrates that ERβ agonist LY500307 inhibited the tumor growth and the effect was more pronounce in combination with aromatase inhibitor letrozole. Ex-vivo model of E0771 cells showed that LY500307 has potential to dramatically reduce the proliferation of mouse mammary tumor growth.Together, these results identify potential molecular targets and anticancer effects of ERβ agonists in mouse mammary tumors. Citation Format: Ramasamy K, Samayoa C, Krishnegowda NK, Thurlapati A, Vadlamudi RK, Tekmal RR. Estrogen receptor β agonists inhibits syngeneic mammary tumor growth through cell-cycle arrest by modulating cell-cycle regulators [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-04-01.