title: Vitamin C and alpha-naphthoflavone prevent estrogen-induced mammary tumors and decrease oxidative stress in female ACI rats.
abstract: The mechanisms underlying the pathogenesis of estrogen-induced breast carcinogenesis remain unclear. The present study investigated the roles of estrogen metabolism and oxidative stress in estrogen-mediated mammary carcinogenesis in vivo. Female August Copenhagen Irish (ACI) rats were treated with 17beta-estradiol (E(2)), the antioxidant vitamin C, the estrogen metabolic inhibitor alpha-naphthoflavone (ANF), or cotreated with E(2) + vitamin C or E(2) + ANF for up to 8 months. E(2) (3 mg) was administered as an subcutaneous implant, ANF was given via diet (0.2%) and vitamin C (1%) was added to drinking water. At necropsy, breast tumor incidence in the E(2), E(2) + vitamin C and E(2) + ANF groups was 82, 29 and 0%, respectively. Vitamin C and ANF attenuated E(2)-induced alterations in oxidative stress markers in breast tissue, including 8-iso-prostane F(2alpha) formation and changes in the activities of antioxidant enzymes superoxide dismutase and glutathione peroxidase. Quantification of 2-hydroxyestradiol (2-OHE(2)) and 4-hydroxyestradiol (4-OHE(2)) formation in breast tissue confirmed that ANF inhibited 4-hydroxylation of E(2) and decreased formation of the highly carcinogenic 4-OHE(2). These results demonstrate that antioxidant vitamin C reduces the incidence of estrogen-induced mammary tumors, increases tumor latency and decreases oxidative stress in vivo. Further, our data indicate that ANF completely abrogates breast cancer development in ACI rats. The present study is the first to demonstrate the inhibition of breast carcinogenesis by antioxidant vitamin C or the estrogen metabolic inhibitor ANF in an animal model of estrogen-induced mammary carcinogenesis. Taken together, these results suggest that E(2) metabolism and oxidant stress are critically involved in estrogen-induced breast carcinogenesis.
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 60 Haven Avenue, New York, NY 10032, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Mense
authors.forename: Bhupendra
authors.initials: B
authors.lastname: Singh
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Remotti
authors.forename: Xinhua
authors.initials: X
authors.lastname: Liu
authors.forename: Hari K
authors.initials: HK
authors.lastname: Bhat
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001205:Ascorbic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D001571:Benzoflavones / Q000494:pharmacology* / Q000627:therapeutic use; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*; D002393:Estrogens, Catechol; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D009376:Neoplasms, Hormone-Dependent / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D011912:Rats, Inbred ACI
chemical_list: D000975:Antioxidants; D001571:Benzoflavones; D002393:Estrogens, Catechol; C075750:8-epi-prostaglandin F2alpha; D004958:Estradiol; C011512:alpha-naphthoflavone; C001390:2-hydroxyestradiol; D015237:Dinoprost; C014036:4-hydroxyestradiol; D001205:Ascorbic Acid