Epigenetic reactivation of estrogen receptor-α (ERα) by genistein enhances hormonal therapy sensitivity in ERα-negative breast cancer

Abstract

BackgroundEstrogen receptor-α (ERα)-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 ERα-positive breast cancer cells. However, the role of GE in ERα-negative breast cancer remains unknown.MethodsWe have evaluated the in vitro and in vivo epigenetic effects of GE on ERα 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.ResultsWe 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. Consistently, dietary GE significantly prevented cancer development and reduced the growth of ERα-negative mouse breast tumors. Dietary GE further enhanced TAM-induced anti-cancer efficacy due at least in part to epigenetic ERα reactivation.ConclusionsOur studies suggest that soybean genistein can epigenetically restore ERα 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 ERα-negative breast cancer which will provide more effective options in breast cancer therapy.

The antiproliferative and proapoptotic effects of cladosporols A and B are related to their different binding mode as PPARγ ligands

“…All deuterated solvents (DMSO-d 6 , 99.9 atom%; D 2 O, 99.9 atom %) were purchased from Sigma-Aldrich. 1 H NMR spectra were recorded at 25°C using a Bruker Avance 600 MHz instrument.…”

“…Therefore, cladosporols A and B were dissolved in D 2 O/DMSOd 6 (1:1, v/v) and analyzed for 24 h at 25°C by 1 H NMR spectroscopy. The spectra were recorded every hour and the peak integrated areas were compared with that obtained with tetramethylsilane (TMS) used as an internal standard.…”

“…In addition, they are very useful in the management of cancer patients either alone or in combination with known molecules [4][5][6].…”

Novel Combination of Withaferin A and Sulforaphane Inhibits Epigenetic Machinery, Cellular Viability and Induces Apoptosis of Breast Cancer Cells

“…Recently, Esmaeili reported that epigallocatechin gallate (EGCG), a component of green tea, is responsible for the reversal of chemoresistance in breast cancer cells [7]. Moreover, our studies have indicated that genistein, a soybean isoflavone, is instrumental in the reactivation of estrogen receptor alpha (ERα) in triple-negative breast cancer cells, which enhanced the efficacy of hormone therapy in these cells [8]. The regulation of DNMTs and HDACs was shown to be an important factor in ERα conversion in these cells.…”

Nutraceuticals: Curative Integrative Cancer Treatment

“…Daidzein, genistein, and kievitone have structural similarities to 17β-estradiol (E2). Daidzein, genistein, and kievitone elevate sex hormonebinding globulin (SHBG), are anti-oxidants, apoptotic, and inhibit angiogenesis, topoisomerase, tyrosine kinase, EGFR, IGFR-1 and NF-κB signaling pathways [26,43,58]. Genistein and other isoflavones preferentially bind the anti-proliferative estrogen receptor β (ER-β), functioning as SERMs, potentially balancing estrogen receptor α (ER-α)'s hyperproliferative effects in adipose tissue, the bone, breast, liver, ovarian thecal cells, prostate, and uterus [59].…”