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, 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 of resveratrol-mediated protection against estrogen-induced breast carcinogenesis. Female ACI rats were treated with 17β-estradiol (E2), resveratrol, and resveratrol + E2 for 8 months. Co-treatment of rats with resveratrol + E2 significantly increased tumor latency and reduced E2-induced breast tumor development. Resveratrol treatment upregulated nuclear factor erythroid 2-related factor 2 (NRF2) expression and inhibited E2-mediated changes in activities of antioxidant enzymes in the mammary tissues. Resveratrol upregulated NRF2-regulated antioxidant genes NQO1, SOD3, and OGG1 a gene involved in protection against oxidative DNA damage. Resveratrol also prevented E2-mediated inhibition of detoxification genes flavin monooxygenase 1, aldehyde oxidase 1 and monoamine oxidase b1. Resveratrol treatment upregulated NRF2 expression by inhibiting E2-mediated alterations in NRF2 promoter methylation pattern and by reverting E2-mediated increased expression of NRF2 targeting micoRNA miR-93. Resveratrol treatment induced apoptosis and inhibited E2-mediated increase in 8-OHdG levels, a marker of oxidative DNA damage. Decreased colony formation, mammosphere formation and cell migration in resveratrol-treated MCF-10A cells further suggest protective role of resveratrol against E2-induced mammary carcinogenesis. Taken together, these results suggest that resveratrol inhibits E2-induced breast carcinogenesis through inhibition of oxidative stress and activation of NRF2-mediated protective pathways.
Citation Format: Bhupendra Singh, Amruta Ronghe, Anwesha Chatterjee, Hari K. Bhat. Resveratrol inhibits oxidative stress and prevents estrogen-induced breast carcinogenesis via activation of NRF2-mediated protective pathways. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3696. doi:10.1158/1538-7445.AM2013-3696