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. Estrogeninduced 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 ACI rats were treated with 17β-estradiol (E2), Res, and Res+E2 for 8 months. Co-treatment 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 NRF2 in mammary tissues. Expression of NRF2-regulated antioxidant genes NQO1, SOD3, and OGG1 that is 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. siRNA-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.