Regulation of BRCA‐1 by Xenobiotic and Dietary Ligands of the Aryl Hydrocarbon Receptor

Abstract

The BRCA‐1 protein is involved in repair of DNA damage and mutations of the BRCA‐1 gene confer a high risk of developing breast cancer. Interestingly, mutations of BRCA‐1 account for only 5‐10% of breast cancer cases, whereas sporadic breast tumors represent the remaining 90‐95%. In sporadic breast cancers there is silencing of BRCA‐1 in the absence of mutations. Factors contributing to this etiology include the environmental ligands of the aryl hydrocarbon receptor (AhR) 2,3,7,8 tetrachlorodibenzene(p)dioxin (TCDD) and polycyclic aryl hydrocarbons (PAHs). Dietary antagonists of the AhR with potential protective effects include the phytoalexin resveratrol and 3,3′‐diindolylmethane (DIM), the condensation product of indole‐3‐carbinol. The objective of this study was to investigate the mechanisms responsible for repression of BRCA‐1 expression by the activated AhR. Results of DNA binding studies in MCF‐7 breast cancer cells documented that TCDD‐induced the association of the AhR to xenobiotic responsive elements (XRE) harbored in the BRCA‐1 promoter region. The cotreatment with resveratrol (5, 10, 20µM) reduced AhR recruitment in a dose‐dependent fashion. We are investigating the chromatin modifications induced by the AhR at the BRCA‐1 gene and the preventative effects of resveratrol. These studies may have implications for the use of dietary AhR ligands in prevention of BRCA‐1 silencing induced by AhR agonists.Grant Funding SourceSusan G. Komen Breast Cancer Foundation and Arizona Biomedical Research Commission