HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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.
AuthorsAndreas J Papoutsis, Jamie L Borg, Ornella I Selmin, Donato F Romagnolo
JournalThe Journal of nutritional biochemistry (J Nutr Biochem) Vol. 23 Issue 10 Pg. 1324-32 (Oct 2012) ISSN: 1873-4847 [Electronic] United States
PMID22197621 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier Inc. All rights reserved.
Chemical References
  • BRCA1 Protein
  • BRCA1 protein, human
  • Carcinogens
  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Ligands
  • Polychlorinated Dibenzodioxins
  • Receptors, Aryl Hydrocarbon
  • Stilbenes
  • Estradiol
  • Resveratrol
Topics
  • BRCA1 Protein (genetics)
  • Breast Neoplasms (pathology)
  • Carcinogens (toxicity)
  • DNA Methylation
  • Estradiol (pharmacology)
  • Estrogen Receptor alpha (genetics)
  • Exons
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing (drug effects)
  • Humans
  • Ligands
  • MCF-7 Cells
  • Polychlorinated Dibenzodioxins (toxicity)
  • Promoter Regions, Genetic
  • Receptors, Aryl Hydrocarbon (genetics, metabolism)
  • Response Elements
  • Resveratrol
  • Sequence Analysis, DNA
  • Stilbenes (pharmacology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: