Abstract 4212: Prevention of estrogen-induced breast cancer by antioxidants: Role of N-quinone oxidoreductase 1 (NQO1)

Abstract

Abstract The importance of estrogens in the etiology of breast cancer is widely recognized. However, the exact mechanisms underlying the initiation and progression of estrogen-related cancers are not clear. Literature evidence and our studies strongly support the role of estrogen metabolism-mediated oxidative stress in estrogen-induced breast carcinogenesis. The objective of the current study was to characterize the role of NQO1 in the prevention of estrogen-induced DNA damage and mammary tumorigenesis by antioxidants vitamin C or butylated hydroxyanisole (BHA). NQO1 converts 17β-estradiol (E2)-quinones back to E2-catechols, thus making E2-quinones unavailable for oxidant damage. Female ACI rats were treated with E2 (3 mg); vitamin C (1% in drinking water); E2 + vitamin C; BHA (0.7% in diet); and E2 + BHA for up to 8 months. The female ACI rat is an established animal model to study the mechanisms of E2-induced breast cancer. No tumors were detected in the sham control, vitamin C and BHA treatment groups whereas in the E2 + vitamin C, E2 + BHA, and E2 treatment groups, the breast tumor incidences were 29, 24 and 82% respectively. mRNA and protein expression of NQO1 was analyzed in breast and breast tumor tissues of rats treated with E2 and antioxidants vitamin C or BHA. NQO1 was suppressed in E2-exposed mammary tissue after treatment of rats with E2 for 8 months and in mammary tumors. This suppression was overcome by co-treatment of rats with E2 and vitamin C or BHA. NQO1 enzyme activity was unchanged in mammary tissue of rats from all the treatment groups. However, NQO1 enzyme activity was decreased in E2-induced mammary tumors. Catechol-O-methyltransferase (COMT) activity was unchanged in the mammary tissue of all the groups except in the E2-treated group. Vitamin C or BHA co-treatment significantly decreased E2-mediated increase in 8-hydroxydeoxyguanosine (8-OHdG, an oxidative DNA damage marker) levels in mammary tissue. To investigate the relationship between NQO1 and 8-OHdG damage, human breast epithelial cell line MCF10A was treated with E2, vitamin C, BHA, dicumarol (NQO1 inhibitor), E2 + vitamin C, and E2 + BHA. E2 and dicumarol significantly increased 8-OHdG levels in MCF-10A cells whereas co-treatment with E2 and antioxidants reverted them back to the normal levels. Our studies suggest a protective role of NQO1 in E2-induced DNA damage and breast carcinogenesis. NQO1 may thus have a unique potential in the development of therapeutic strategies for the prevention of estrogen-induced neoplasia. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4212. doi:10.1158/1538-7445.AM2011-4212