Genistein PreventsCpG Methylation and Proliferation in Human Breast Cancer Cells with Activated Aromatic Hydrocarbon Receptor.
Curr Dev Nutr. 2017 Jun ;1(6):e000562. Epub 2017 May 19. PMID: 29955703
Donato F Romagnolo
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.We investigated the regulation ofby the soy isoflavone genistein (GEN) in human estrogen receptorα (ERα)-positive Michigan Cancer Foundation-7 (MCF-7) and ERα-negative sporadic University of Arizona Cell Culture-3199 (UACC-3199) breast cancer cells, respectively, with inducible and constitutively active AhR.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 oncytosine-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 andα-naphthoflavone (αNF; 7,8-benzoflavone), a synthetic flavone and AhR antagonist, onexpression and CpG methylation, cyclin D1, and cell growth. Finally, we examined the effects of GEN andαNF on, AhR-inducible cytochrome P450 ()-1A1 () and, andmRNA expression.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 reducedCpG methylation and cell proliferation associated with increased p53. In UACC-3199 cells, GEN reducedand estrogen receptor-1 () CpG methylation, cyclin D1, and cell growth while inducing BRCA-1 and.Results suggest preventative effects for GEN and EGCG againstCpG methylation and downregulation in ERα-positive breast cancer cells with activated AhR. GEN and flavone antagonists of AhR may be useful for reactivation ofand ERα via CpG demethylation in ERα-negative breast cancer cells harboring constitutively active AhR.