title: Resveratrol inhibits estrogen-induced breast carcinogenesis through induction of NRF2-mediated protective pathways.
abstract: The importance of estrogens in the etiology of breast cancer is widely recognized. Estrogen-induced oxidative stress has been implicated in this carcinogenic process. Resveratrol (Res), a natural antioxidant phytoestrogen has chemopreventive effects against a variety of illnesses including cancer. The objective of the present study was to characterize the mechanism(s) of Res-mediated protection against estrogen-induced breast carcinogenesis. Female August Copenhagen Irish rats were treated with 17β-estradiol (E2), Res and Res + E2 for 8 months. Cotreatment of rats with Res and E2 inhibited E2-mediated proliferative changes in mammary tissues and significantly increased tumor latency and reduced E2-induced breast tumor development. Resveratrol treatment alone or in combination with E2 significantly upregulated expression of nuclear factor erythroid 2-related factor 2 (NRF2) in mammary tissues. Expression of NRF2-regulated antioxidant genes NQO1, SOD3 and OGG1 that are involved in protection against oxidative DNA damage was increased in Res- and Res + E2-treated mammary tissues. Resveratrol also prevented E2-mediated inhibition of detoxification genes AOX1 and FMO1. Inhibition of E2-mediated alterations in NRF2 promoter methylation and expression of NRF2 targeting miR-93 after Res treatment indicated Res-mediated epigenetic regulation of NRF2 during E2-induced breast carcinogenesis. Resveratrol treatment also induced apoptosis and inhibited E2-mediated increase in DNA damage in mammary tissues. Increased apoptosis and decreased DNA damage, cell migration, colony and mammosphere formation in Res- and Res + E2-treated MCF-10A cells suggested a protective role of Res against E2-induced mammary carcinogenesis. Small-interfering RNA-mediated silencing of NRF2 inhibited Res-mediated preventive effects on the colony and mammosphere formation. Taken together, these results suggest that Res inhibits E2-induced breast carcinogenesis via induction of NRF2-mediated protective pathways.
authors.affiliation: Department of Genetics, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA, Institute of Comparative Medicine, Columbia University, New York, NY 10032, USA and Division of Pharmacology and Toxicology, School of Pharmacy and School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Bhupendra
authors.initials: B
authors.lastname: Singh
authors.affiliation: Institute of Comparative Medicine, Columbia University, New York, NY 10032, USA and.
authors.forename: Rivka
authors.initials: R
authors.lastname: Shoulson
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy and.
authors.forename: Anwesha
authors.initials: A
authors.lastname: Chatterjee
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy and.
authors.forename: Amruta
authors.initials: A
authors.lastname: Ronghe
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy and.
authors.forename: Nimee K
authors.initials: NK
authors.lastname: Bhat
authors.affiliation: School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Dim
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy and bhath@umkc.edu.
authors.forename: Hari K
authors.initials: HK
authors.lastname: Bhat
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000975:Antioxidants; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D019175:DNA Methylation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects; D004967:Estrogens / Q000633:toxicity*; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011912:Rats, Inbred ACI; D011919:Rats, Inbred Strains; D060888:Real-Time Polymerase Chain Reaction; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013267:Stilbenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D016588:Anticarcinogenic Agents; D000975:Antioxidants; D004967:Estrogens; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013267:Stilbenes; D000077185:Resveratrol