Synergistic epigenetic reactivation of estrogen receptor-α (ERα) by combined green tea polyphenol and histone deacetylase inhibitor in ERα-negative breast cancer cells

Background: The status of estrogen receptor-alpha (ER alpha) is critical to the clinical prognosis and therapeutic approach in breast cancer. ER alpha-negative breast cancer is clinically aggressive and has a poor prognosis because of the lack of hormone target-directed therapies. Previous studies have shown that epigenetic regulation plays a major role in ER alpha silencing in human breast cancer cells. Dietary green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG), is believed to be an anticancer agent in part through its regulation of epigenetic processes. Results: In our current studies, we found that EGCG can reactivate ER alpha expression in ER alpha-negative MDA-MB-231 breast cancer cells. Combination studies using EGCG with the histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), revealed a synergistic effect of reactivation of ER alpha expression in ER alpha-negative breast cancer cells. Reactivation of ER alpha expression by EGCG and TSA treatment was found to sensitize ER alpha-dependent cellular responses to activator 17 beta-estradiol (E-2) and antagonist tamoxifen in ER alpha-negative breast cancer cells. We also found that EGCG can lead to remodeling of the chromatin structure of the ER alpha promoter by altering histone acetylation and methylation status thereby resulting in ER alpha reactivation. A decreased binding of the transcription repressor complex, Rb/p130-E2F4/5-HDAC1-SUV39H1-DNMT1, in the regulatory region of the ER alpha promoter also contributes to ER alpha transcriptional activation through treatment with EGCG and/or TSA. Conclusions: Collectively, these studies show that green tea EGCG can restore ER alpha expression by regulating epigenetic mechanisms, and this effect is enhanced when combined with an HDAC inhibitor. This study will facilitate more effective uses of combination approaches in breast cancer therapy and will help to explore more effective chemotherapeutic strategies toward hormone-resistant breast cancer.