Resveratrol inhibits estrogen-induced breast carcinogenesis through induction of NRF2-mediated protective pathways

Autor: Bhupendra Singh, Daniel C. Dim, Nimee K. Bhat, Hari K. Bhat, Rivka L. Shoulson, Amruta Ronghe, Anwesha Chatterjee
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Cancer Research
DNA damage
NF-E2-Related Factor 2
Blotting
Western
Original Manuscript
Apoptosis
Resveratrol
Biology
medicine.disease_cause
Real-Time Polymerase Chain Reaction
Antioxidants
Epigenesis
Genetic
chemistry.chemical_compound
Cell Movement
Stilbenes
medicine
Tumor Cells
Cultured
Animals
Anticarcinogenic Agents
Humans
Epigenetics
RNA
Messenger
RNA
Small Interfering
skin and connective tissue diseases
Cell Proliferation
Cell growth
Reverse Transcriptase Polymerase Chain Reaction
Mammary Neoplasms
Experimental
Estrogens
Rats
Inbred Strains
General Medicine
DNA Methylation
Molecular biology
Rats
Inbred ACI
Cell Transformation
Neoplastic
chemistry
DNA methylation
Cancer research
Female
Carcinogenesis
Oxidative stress
hormones
hormone substitutes
and hormone antagonists
Signal Transduction
Popis: 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.
Databáze: OpenAIRE
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