Epigenetic mechanisms may contribute to reduced expression of the tumor suppressor gene BRCA-1 in sporadic breast
cancers. Through environmental exposure and diet, humans are exposed to
xenobiotics and food compounds that bind the
aromatic hydrocarbon receptor (AhR). AhR-
ligands include the
dioxin-like and
tumor promoter 2,3,7,8
tetrachlorodibenzo-p-dioxin (
TCDD). The activated AhR regulates transcription through binding to
xenobiotic response elements (XREs=GCGTG) and interactions with transcription cofactors. Previously, we reported on the presence of several XREs in the proximal BRCA-1 promoter and that the expression of endogenous AhR was required for silencing of BRCA-1 expression by
TCDD. Here, we document that in
estrogen receptor-α-positive and BRCA-1 wild-type MCF-7
breast cancer cells, the treatment with
TCDD attenuated 17β-estradiol-dependent stimulation of BRCA-1
protein and induced hypermethylation of a CpG island spanning the BRCA-1 transcriptional start site of exon-1a. Additionally, we found that
TCDD enhanced the association of the AhR;
DNA methyl
transferase (DNMT)1, DNMT3a and DNMT3b; methyl
binding protein (MBD)2; and trimethylated H3K9 (H3K9me3) with the BRCA-1 promoter. Conversely, the phytoalexin
resveratrol, selected as a prototype dietary AhR antagonist, antagonized at physiologically relevant doses (1 μmol/L) the
TCDD-induced repression of BRCA-1
protein, BRCA-1 promoter methylation and the recruitment of the AhR, MBD2, H3K9me3 and DNMTs (1, 3a and 3b). Taken together, these observations provide mechanistic evidence for AhR agonists in the establishment of BRCA-1 promoter hypermethylation and the basis for the development of prevention strategies based on AhR antagonists.