title: BRCA-1 promoter hypermethylation and silencing induced by the aromatic hydrocarbon receptor-ligand TCDD are prevented by resveratrol in MCF-7 cells.
abstract: 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.
authors.affiliation: Department of Nutritional Sciences, The University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Papoutsis
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Borg
authors.forename: Ornella I
authors.initials: OI
authors.lastname: Selmin
authors.forename: Donato F
authors.initials: DF
authors.lastname: Romagnolo
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000473:pathology; D002273:Carcinogens / Q000633:toxicity; D019175:DNA Methylation; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics; D005091:Exons; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011401:Promoter Regions, Genetic; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D000077185:Resveratrol; D017422:Sequence Analysis, DNA; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D002273:Carcinogens; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D008024:Ligands; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D013267:Stilbenes; D004958:Estradiol; D000077185:Resveratrol