Abstract 4029: Enhanced chemosensitivity of estrogen receptor-α (ERα)-negative breast cancer through soybean genistein-induced epigenetic reactivation of ERα

Abstract

Abstract Estrogen receptor-α (ERα)-negative breast cancer is clinically aggressive and has a poor prognosis due to the lack of estrogen target-directed therapies. The soybean isoflavone, genistein (GE), has been shown to prevent and inhibit breast cancer and recent studies have suggested that GE can enhance the anticancer capacity of an estrogen antagonist, tamoxifen (TAM), especially in ERα-positive breast cancer cells. However, the role of GE in ERα-negative breast cancer remains unknown. In our current studies, we found that GE can reactivate ERα expression and this effect was synergistically enhanced when combined with a histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), in ERα-negative MDA-MB-231 breast cancer cells. GE treatment also re-sensitized ERα-dependent cellular responses to activator 17β-estradiol (E2) and antagonist TAM. Further studies revealed that GE can lead to remodeling of the chromatin structure in the ERα promoter thereby contributing to ERα reactivation. The global enzymatic activities for HDACs and DNA methyltransferases (DNMTs) mediated by GE were altered to favor ERα up-regulation. Consistently, dietary GE significantly reduced the growth of ERα-negative mouse xenograft tumors due at least in part to ERα reactivation. The combination of GE with TAM had more prominent effects on delaying tumor growth than either treatment alone. Collectively, our studies suggest that soybean genistein can epigenetically restore ERα expression, which in turn increases TAM-dependent anti-estrogen chemosensitivity. The results from our studies revealed a novel chemotherapeutic combination approach using bioactive soybean product and anti-hormone therapy in refractory ERα-negative breast cancer which will provide more effective options in breast cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4029. doi:1538-7445.AM2012-4029