Epigenetic reactivation of estrogen receptor-a (ERa) by genistein enhances hormonal therapy sensitivity in ERa-negative breast cancer.

Li Y1, Meeran SM, Patel SN, Chen H, Hardy TM, Tollefsbol TO.
Source: Mol Cancer
Publication Date: (2013)
Issue: 4: 12:9
Research Area:
Basic Research
Cells used in publication:
Epithelial, mammary, human (HMEC)
Species: human
Tissue Origin: breast
BACKGROUND: Estrogen receptor-a (ERa)-negative breast cancer is clinically aggressive and normally does not respond to conventional 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 ERa-positive breast cancer cells. However, the role of GE in ERa-negative breast cancer remains unknown. METHODS: We have evaluated the in vitro and in vivo epigenetic effects of GE on ERa reactivation by using MTT assay, real-time reverse transcription-polymerase chain reaction (RT-PCR) assay, western-blot assay, immunoprecipitation (ChIP) assay, immunohistochemistry and epigenetic enzymatic activity analysis. Preclinical mouse models including xenograft and spontaneous breast cancer mouse models were used to test the efficacy of GE in vivo. RESULTS: We found that GE can reactivate ERa expression and this effect was synergistically enhanced when combined with a histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), in ERa-negative MDA-MB-231 breast cancer cells. GE treatment also re-sensitized ERa-dependent cellular responses to activator 17ß-estradiol (E2) and antagonist TAM. Further studies revealed that GE can lead to remodeling of the chromatin structure in the ERa promoter thereby contributing to ERa reactivation. Consistently, dietary GE significantly prevented cancer development and reduced the growth of ERa-negative mouse breast tumors. Dietary GE further enhanced TAM-induced anti-cancer efficacy due at least in part to epigenetic ERa reactivation. CONCLUSIONS: Our studies suggest that soybean genistein can epigenetically restore ERa expression, which in turn increases TAM-dependent anti-estrogen therapeutic sensitivity in vitro and in vivo. The results from our studies reveal a novel therapeutic combination approach using bioactive soybean product and anti-hormone therapy in refractory ERa-negative breast cancer which will provide more effective options in breast cancer therapy.