Abstract
Abstract Breast cancer is the main cause of cancer-associated mortality in women worldwide. The estrogen receptors play a critical role in normal mammary gland development as well as breast cancer. Over two thirds of all breast cancers express high levels of Estrogen Receptor α (ERα) and are depend on estrogen for growth. Current endocrine therapies aim to decrease estrogen levels with the use aromatase inhibitors or to inhibit ERα signaling with the use of anti-estrogens. Although these treatment options are initially effective, a significant number of patients will present with recurrent disease. Therefore, there is a critical need to identify targeted therapies which will inhibit tumor progression and circumvent therapy resistance. In addition to focusing on ERα, emerging evidence has shed light on the importance of Estrogen Receptor β in breast cancer. Unlike ERα, ERβ has tumor suppressing activity, therefore targeting ERβ with selective agonists may provide therapeutic benefit in the treatment of breast cancer. The objective of this study was to investigate the effects of selective ERβ agonists in distinct breast cancer models. Liquiritigenin and S-Equol are selective plant-derived ERβ agonists currently in clinical trials for the relief of symptoms associated with menopause, and for the treatment of benign prostate hyperplasia. Additionally, LY500307, a synthetic ERβ agonist is currently in clinical trials and has been shown to be well tolerated. To test the effects of ERβ agonists on growth, we carried out cell growth assays using various cell lines. MCF7aro and ZR-75aro cells were used as models of post-menopausal breast cancer given their ability to synthesize their own estrogens. A letrozole resistant cell line was used to determine if ERβ agonists could inhibit the growth of therapy resistant cells. Additionally, we used a syngeneic tumor mouse model to investigate if ERβ agonist could inhibit tumor growth in a model with an intact immune system. Our results demonstrate that both, plant-derived and synthetic, ERβ agonists can inhibit the growth of breast cancer cells, including those that over express aromatase, and are resistant to letrozole. The synthetic ERβ agonist was able to inhibit growth at much lower doses, overcoming a critical barrier presented by the plant derived agonists. Our mechanistic studies show that ERβ agonists can alter ERα and ERβ levels, which shift the α/β ratio to a more tumor suppressive state. We also found that these compounds affect cell cycle through cyclin D1 and p27. Additionally, we also saw induction of apoptosis and increased p53 levels. Our studies evaluated the effects of ERβ agonists in various breast cancer cell lines, and our results suggest that targeting ERβ may be a valuable therapeutic option for the treatment of breast cancer. Citation Format: Cathy Samayoa, Naveen Krishnegowda, Ratna Vadlamudi, Rajeshwar Tekmal. Evaluating estrogen receptor β agonists for the treatment of breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3457. doi:10.1158/1538-7445.AM2015-3457
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