Resveratrol Prevents Epigenetic Silencing of BRCA‐1 by the Activated AhR in Breast Cancer Cells

The BRCA‐1 protein is a tumor suppressor involved in repair of DNA damage. Changes in DNA methylation and histone codes are epigenetic events that may contribute to its reduced expression in sporadic breast tumors. The activation of the AhR has been suggested as a risk for breast cancer. Many natural dietary bioactive compounds including the phytoalexin resveratrol (Res) and environmental xenobiotics bind the AhR. In MCF‐7 breast cancer cells we investigated the influence of TCDD‐dependent activation of the AhR on epigenetic regulation of the BRCA‐1 gene and the preventative effects of Res. We found that TCDD‐dependent activation and recruitment of the AhR to the BRCA‐1 promoter inhibited induction of BRCA‐1 protein expression. This repression was accompanied by reduced occupancy at the BRCA‐1 promoter of DNA‐methyltransferase‐1 (DNMT1) and methyl‐binding domain protein‐2 (MBD2). The TCDD‐dependent repression of BRCA‐1 was reversed by siRNA for the AhR and DNMT1, or treatment with Res. Additionally, we observed that the tea polyphenol (−)‐epigallocatechin‐3‐gallate (EGCG) and the soy isoflavone genistein reduced recruitment of DNMT1 to the BRCA‐1 promoter. These results support the hypothesis that activation of the AhR leads to epigenetic silencing of the BRCA‐1 gene accompanied by promoter methylation and histone deacetylation, and that these effects may be prevented by Res or reversed by dietary agents.