Resveratrol prevents epigenetic silencing of BRCA-1 by the aromatic hydrocarbon receptor in human breast cancer cells

Andreas J. Papoutsis, Sarah D. Lamore, Georg T Wondrak, Ornella Selmin, Donato Romagnolo

Research output: Contribution to journalArticle

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Abstract

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-a (ERa)-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 17b-estradiol (E2)-dependent stimulation of BRCA-1 transcription and protein levels. These inhibitory effects are paralleled by reduced occupancy of ERa, 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.

Original languageEnglish (US)
Pages (from-to)1607-1614
Number of pages8
JournalJournal of Nutrition
Volume140
Issue number9
DOIs
StatePublished - Sep 2010

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Aromatic Hydrocarbons
Epigenomics
Breast Neoplasms
DNA Breaks
Methyltransferases
Xenobiotics
Estrogen Receptors
Ligands
resveratrol
Complex Mixtures
Histones
Genes
DNA Damage
Estradiol
Neoplasms
Carrier Proteins
Proteins
Diet
DNA

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Nutrition and Dietetics

Cite this

Resveratrol prevents epigenetic silencing of BRCA-1 by the aromatic hydrocarbon receptor in human breast cancer cells. / Papoutsis, Andreas J.; Lamore, Sarah D.; Wondrak, Georg T; Selmin, Ornella; Romagnolo, Donato.

In: Journal of Nutrition, Vol. 140, No. 9, 09.2010, p. 1607-1614.

Research output: Contribution to journalArticle

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