Abstract 1820: Investigating the role of estrogen receptor β agonists in the prevention and treatment of breast cancer

Abstract

Abstract Breast Cancer is the primary cause of cancer-associated mortality worldwide. In the United States alone, more than 250,000 women are diagnosed every year. Asian women have the lowest incidence rates. However, their rates increase to those of the US within one generation after migration. Suggesting that diet and lifestyle are major contributing factors in breast cancer risk. Since Asian women consume high amount of soy when compared to other populations, perhaps compounds found in soy may have a protective effect that is lost once they adopt a western diet. Recent studies have identified plant-derived compounds from soy and licorice that activate Estrogen Receptor β. Unlike previous ERβ agonists, these novel compounds are selective for ERβ and have been tested for safety in clinical trials. 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. However, in the last decade, the importance of ERβ has emerged. Unlike ERα, ERβ has been shown to have tumor-suppressive function in various cancers, including breast cancer. The objective of this study was to investigate the utility of using ERβ agonists in the prevention and treatment on breast cancer. To investigate the significance of ERβ activation in the prevention of breast cancer, we used an immunocompetent transgenic mouse model of breast cancer. Specifically, HER2/neu overexpressing mice develop premalignant lesions at 4-5 months and tumors starting at month 7. HER2/neu mice were treated with ERβ agonists for 3 months and subsequently mammary glands were analyzed using whole mount and IHC. When compared to controls, ERβ agonist treated mice showed a decrease in branching and ductal hyperplasia, with no change in body weight. These results suggest that ER β agonist treatment is chemopreventive and provided protection against premalignant lesion in the mammary gland. To investigate the utility of ERβ agonists in the treatment of breast cancer, we used in-vitro and in-vivo models systems. Our results demonstrated that treatment with the agonists was able to inhibit the short-term and long-term growth of the breast cancer cell lines; MCF7aro and LTLT which represent post-menopausal breast cancer and letrozole resistant cells, respectively. In addition to growth inhibition, treatment with ERβ agonists also decreased cell migration and invasion. In addition to activating ERβ, we also found that the agonists are also able to increase the expression of ERβ without increasing ERα levels. Our studies also demonstrated that treatment with ERβ agonists modulated key signaling molecules involved in cell death and cell cycle. Our studies suggest that activation of ERβ signaling is a valuable strategy in the treatment and chemoprevention of breast cancer. Citation Format: Cathy Samayoa, Naveen K. Krishnegowda, Ratna K. Vadlamudi, Rajeshwar R. Tekmal. Investigating the role of estrogen receptor β agonists in the prevention and treatment of breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1820.