The status of estrogen receptor-alpha (ERalpha) is critical to the clinical prognosis and therapeutic approach in breast cancer. ERalpha-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 ERalpha 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.

In our current studies, we found that EGCG can reactivate ERalpha expression in ERalpha-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 ERalpha expression in ERalpha-negative breast cancer cells. Reactivation of ERalpha expression by EGCG and TSA treatment was found to sensitize ERalpha-dependent cellular responses to activator 17beta-estradiol (E2) and antagonist tamoxifen in ERalpha-negative breast cancer cells. We also found that EGCG can lead to remodeling of the chromatin structure of the ERalpha promoter by altering histone acetylation and methylation status thereby resulting in ERalpha reactivation. A decreased binding of the transcription repressor complex, Rb/p130-E2F4/5-HDAC1-SUV39H1-DNMT1, in the regulatory region of the ERalpha promoter also contributes to ERalpha transcriptional activation through treatment with EGCG and/or TSA.

Collectively, these studies show that green tea EGCG can restore ERalpha 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.

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