Reactivation of estrogen receptor-alpha (ERalpha) by bioactive dietary compounds through epigenetic mechanisms in ERalpha-negative breast cancer cells

In breast cancer treatment, the presence of the estrogen receptor-alpha (ERα) plays an important role with hormonal-responsive drugs such as tamoxifen. ERα-negative breast cancers are more aggressive not only because of the increased uncontrollable growth but also because of the lack of target-directed treatments. Bioactive dietary components such as green tea polyphenols (GTPs) and sulforaphane (SFN, found in cruciferous vegetables) have been shown to have anti-cancer properties. In this study, we found that the dietary combination of a DNA methyltransferases (DNMTs) inhibitor, GTPs, and a histone deacetylase (HDAC) inhibitor, SFN, dose-dependently inhibited the proliferation of ERα-negative MDA-MB-231 human breast cancer cells. Combination GTPs and SFN treatment also epigenetically reactivated ERα expression in ERα-negative MDA-MB-231 breast cancer cells both at the gene and protein level. A combination of GTPs and SFN significantly inhibited DNMTs and HDAC activity, which is consistently associated with ERα promoter hypomethylation and hyperacetylation, respectively. In addition, a global decrease in methylation was also observed with combination GTPs and SFN treatment. Furthermore, treatment with tamoxifen in combination with GTPs and SFN significantly inhibited ERα-negative MDA-MB-231 breast cancer cellular proliferation and increased apoptosis of the cells. Collectively, this investigation provides a novel combination therapy of GTPs and SFN on hormonal refractory breast cancer with available drugs such as tamoxifen.