Genistein prevents BRCA1 CpG methylation and proliferation in human breast cancer cells with activated aromatic hydrocarbon receptor

Donato F. Romagnolo, Micah G. Donovan, Andreas J. Papoutsis, Tom C. Doetschman, Ornella I. Selmin

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Background: Previous studies have suggested a causative role for agonists of the aromatic hydrocarbon receptor (AhR) in the etiology of breast cancer 1, early-onset (BRCA-1)-silenced breast tumors, for which prospects for treatment remain poor. Objectives: We investigated the regulation of BRCA1 by the soy isoflavone genistein (GEN) in human estrogen receptor a (ERα)-positive Michigan Cancer Foundation-7 (MCF-7) and ERαnegative sporadic University of Arizona Cell Culture-3199 (UACC-3199) breast cancer cells, respectively, with inducible and constitutively active AhR. Methods: In MCF-7 cells, we analyzed the dose- and time-dependent effects of GEN and (-)-epigallocatechin-3-gallate (EGCG) control, selected as prototype dietary DNA methyltransferase (DNMT) inhibitors, on BRCA-1 expression after AhR activation with 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) and in TCDD-washout experiments. We compared the effects of GEN and EGCG on BRCA1 cytosine-phosphate-guanine (CpG) methylation and cell proliferation. Controls for DNA methylation and proliferation were changes in expression of DNMT-1, cyclin D1, and p53, respectively. In UACC-3199 cells, we compared the effects of GEN and a-naphthoflavone (aNF; 7,8-benzoflavone), a synthetic flavone and AhR antagonist, on BRCA1 expression and CpG methylation, cyclin D1, and cell growth. Finally, we examined the effects of GEN and aNF on BRCA1, AhR-inducible cytochrome P450 (CYP)-1A1 (CYP1A1) and CYP1B1, and AhR mRNA expression. Results: In MCF-7 cells, GEN exerted dose- and time-dependent preventative effects against TCDD-dependent downregulation of BRCA-1. After TCDD washout, GEN rescued BRCA-1 protein expression while reducing DNMT-1 and cyclin D1. GEN and EGCG reduced BRCA1 CpG methylation and cell proliferation associated with increased p53. In UACC-3199 cells, GEN reduced BRCA1 and estrogen receptor-1 (ESR1) CpG methylation, cyclin D1, and cell growth while inducing BRCA-1 and CYP1A1. Conclusions: Results suggest preventative effects for GEN and EGCG against BRCA1 CpG methylation and downregulation in ERα-positive breast cancer cells with activated AhR. GEN and flavone antagonists of AhR may be useful for reactivation of BRCA1 and ERα via CpG demethylation in ERα-negative breast cancer cells harboring constitutively active AhR.

Original languageEnglish (US)
Article numbere000562
JournalCurrent Developments in Nutrition
Volume1
Issue number6
DOIs
StatePublished - Jun 1 2017

Keywords

  • AhR
  • BRCA1
  • Breast cancer
  • DNA methylation
  • ESR1
  • Epigenetics
  • Flavonoids
  • Genistein
  • Prevention

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Food Science
  • Nutrition and Dietetics

Fingerprint Dive into the research topics of 'Genistein prevents BRCA1 CpG methylation and proliferation in human breast cancer cells with activated aromatic hydrocarbon receptor'. Together they form a unique fingerprint.

Cite this