Abstract 1115: Epigenetic regulation of BRCA-1 by xenobiotic and dietary ligands of the aryl hydrocarbon receptor

Abstract

Abstract 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 may include environmental ligands of the aryl hydrocarbon receptor (AhR) such as dioxins (ex.2,3,7,8 tetrachlorodibenzene(p)dioxin, TCDD) and polycyclic aryl hydrocarbons (PAHs). Dietary ligands of the AhR with potential protective effects include the phytoalexin resveratrol found in grapes. In this study, we investigated the mechanisms responsible for repression of BRCA-1 expression by the activated AhR. The 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 reduced AhR recruitment in a dose-dependent fashion, prevented the TCDD-dependent repression of BRCA-1 transcription and restored BRCA-1 protein expression. The treatment with TCDD induced the recruitment of histone deacetylase-1, DNA methyltransferase-1, methyl-binding protein-2, and reduced the association of acetylated histone-4 and acetylated histone-K9. These effects were abrogated by cotreatment with resveratrol. We propose that dietary antagonists of the AhR such as resveratrol may be useful in the prevention of epigenetic BRCA-1 silencing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1115.