title: Antioxidant-mediated up-regulation of OGG1 via NRF2 induction is associated with inhibition of oxidative DNA damage in estrogen-induced breast cancer.
abstract: BACKGROUND
  Estrogen metabolism-mediated oxidative stress is suggested to play an important role in estrogen-induced breast carcinogenesis. We have earlier demonstrated that antioxidants, vitamin C (Vit C) and butylated hydroxyanisole (BHA) inhibit 17β-estradiol (E2)-mediated oxidative stress and oxidative DNA damage, and breast carcinogenesis in female August Copenhagen Irish (ACI) rats. The objective of the present study was to characterize the mechanism by which above antioxidants prevent DNA damage during breast carcinogenesis.
  
  
  METHODS
  Female ACI rats were treated with E2; Vit C; Vit C + E2; BHA; and BHA + E2 for up to 240 days. mRNA and protein levels of a DNA repair enzyme 8-Oxoguanine DNA glycosylase (OGG1) and a transcription factor NRF2 were quantified in the mammary and mammary tumor tissues of rats after treatment with E2 and compared with that of rats treated with antioxidants either alone or in combination with E2.
  
  
  RESULTS
  The expression of OGG1 was suppressed in mammary tissues and in mammary tumors of rats treated with E2. Expression of NRF2 was also significantly suppressed in E2-treated mammary tissues and in mammary tumors. Vitamin C or BHA treatment prevented E2-mediated decrease in OGG1 and NRF2 levels in the mammary tissues. Chromatin immunoprecipitation analysis confirmed that antioxidant-mediated induction of OGG1 was through increased direct binding of NRF2 to the promoter region of OGG1. Studies using silencer RNA confirmed the role of OGG1 in inhibition of oxidative DNA damage.
  
  
  CONCLUSIONS
  Our studies suggest that antioxidants Vit C and BHA provide protection against oxidative DNA damage and E2-induced mammary carcinogenesis, at least in part, through NRF2-mediated induction of OGG1.
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Room 5251, Kansas City, MO 64108, USA.
authors.forename: Bhupendra
authors.initials: B
authors.lastname: Singh
authors.forename: Anwesha
authors.initials: A
authors.lastname: Chatterjee
authors.forename: Amruta M
authors.initials: AM
authors.lastname: Ronghe
authors.forename: Nimee K
authors.initials: NK
authors.lastname: Bhat
authors.forename: Hari K
authors.initials: HK
authors.lastname: Bhat
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004249:DNA Damage / Q000502:physiology; D045647:DNA Glycosylases / Q000096:biosynthesis*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis / Q000096:biosynthesis; D004967:Estrogens / Q000633:toxicity*; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D034622:RNA Interference; D051381:Rats; D011912:Rats, Inbred ACI; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; D004967:Estrogens; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D000080242:8-Hydroxy-2'-Deoxyguanosine; D045647:DNA Glycosylases; C483741:OGG1 protein, rat; D003849:Deoxyguanosine