BRCA‐1 Promoter Hypermethylation and Silencing Induced by the Aromatic Hydrocarbon Receptor and Preventative Effects of Resveratrol

Abstract

Epigenetic alterations, such as histone and DNA modifications, have been proposed to play a key role in the onset of breast cancer. In sporadic breast tumors, the BRCA‐1 promoter is hypermethylated, and the expression of BRCA‐1 is reduced in the absence of mutations in the BRCA‐1 gene. Diet is a primary vehicle of exposure to agents that modulate the aromatic hydrocarbon receptor (AhR). Ligands of the AhR include environmental xenobiotics, such as dioxins and polycyclic aromatic hydrocarbons. In addition, many frequently consumed food bioactive components bind the AhR, including the phytoalexin resveratrol (Res). Prenatal exposure to 2,3,7,8 tetrachlorodibenzo (p)dioxin (TCDD) increases the susceptibility to mammary cancers in adult offspring in a rat mammary model. The hypothesis of this project is that the recruitment of the activated AhR to the BRCA‐1 promoter initiates a multistep process leading to chromatin modifications that silence the BRCA‐1 gene through promoter methylation and increase susceptibility of mammary tumors. Conversely, these epigenetic alterations are prevented by Res. Previously we documented that exposure of MCF‐7 cells to TCDD represses estrogen‐dependent activation of BRCA‐1 and induces methylation of CpG islands in the BRCA‐1 promoter. In contrast, Res prevents TCDD‐induced recruitment of the AhR; DNA methyltransferase (DNMT)‐1, DNMT3a, and DNMT3b to the BRCA‐1 gene; and BRCA‐1 promoter methylation. We report that prenatal exposure to TCDD in Sprague Dawley rats decreases whereas Res increases BRCA‐1 protein expression in mammary tissue. In addition to Res antagonizing these effects in mammary tissue, we report that it increases the recruitment of the aromatic hydrocarbon receptor repressor (AHRR) which may play a role in inhibiting the translocation of the AhR to xenobiotic responsive elements (XRE) harbored in the BRCA‐1 promoter.