The BRCA-1
protein is a
tumor suppressor involved in repair of DNA damage. Epigenetic mechanisms contribute to its reduced expression in sporadic
breast tumors. Through diet, humans are exposed to a
complex mixture of
xenobiotics and natural
ligands of the
aromatic hydrocarbon receptor (AhR), which contributes to the etiology of various types of
cancers. The AhR binds
xenobiotics, endogenous
ligands, and many natural dietary bioactive compounds, including the phytoalexin
resveratrol (Res). In
estrogen receptor- alpha (ER alpha )-positive and BRCA-1 wild-type MCF-7
breast cancer cells, we investigated the influence of AhR activation with the agonist 2,3,7,8 tetrachlorobenzo(
p)dioxin (
TCDD) on epigenetic regulation of the BRCA-1 gene and the preventative effects of Res. We report that activation and recruitment of the AhR to the BRCA-1 promoter hampers
17 beta -estradiol (E2)-dependent stimulation of BRCA-1 transcription and
protein levels. These inhibitory effects are paralleled by reduced occupancy of ER alpha , acetylated
histone (AcH)-4, and AcH3K9. Conversely, the treatment with
TCDD increases the association of mono-methylated-H3K9, DNA-methyltransferase-1 (DNMT1), and methyl-binding domain protein-2 with the BRCA-1 promoter and stimulates the accumulation of
DNA strand breaks. The AhR-dependent repression of BRCA-1 expression is reversed by small interference for the AhR and DNMT1 or pretreatment with Res, which reduces
TCDD-induced
DNA strand breaks. These results support the hypothesis that epigenetic silencing of the BRCA-1 gene by the AhR is preventable with Res and provide the molecular basis for the development of dietary strategies based on natural AhR antagonists.