Abstract LB-64: Selective estrogen receptor modulators (SERMs) act as breast cancer chemopreventive agents by attenuating oxidative estrogen metabolism

Abstract

Abstract Possibility of developing hormone dependent cancer in women will increase with long term exposure to endogenous estrogens. Estrogen induced, estrogen receptor (ER) mediated cell proliferation (hormonal pathway) and formation of reactive estrogen metabolites (chemical pathway) are believed to contribute to estrogen carcinogenesis. Estrogens are oxidized to the catechols, 2-hydroxyestradiol (2-OHE2) and 4-hydroxyestradiol (4-OHE2) by P450 1A1/1A2 and P450 1B1 respectively. Both catechols are further oxidized to form electrophilic o-quinones which can react with DNA and proteins, while 4 hydroxyestradiol O-quinone (4-OHE2-Q) is considered as the ultimate carcinogen. Selective Estrogen Receptor Modulators (SERMs) are used in cancer chemoprevention and in the treatment of post menopausal osteoporosis. The current study focuses on elucidating the influence of clinical and pre clinical benzothiophene SERMs on oxidative estrogen metabolism in ER negative non tumerigenic human breast epithelial cells (MCF-10A). Upon exposure to 17β-estradiol (E2), MCF-10A cells transformed into a malignant phenotype and showed anchorage independent colony growth in soft agar. After treatment of MCF-10A cells with E2 and SERMs, estrogen metabolites were analyzed using a sensitive LC-MS/MS method. Among the SERMs tested, raloxifene and desmethylarzoxifen (DMA) showed a significant reduction in catechol estrogen formation whereas 4′F-DMA had little effect. Furthermore, raloxifene and DMA significantly inhibited E2 induced malignant transformation and reactive oxygen species formation in MCF-10A cells. These data suggest that raloxifene and DMA possess chemopreventive activity through inhibition of genotoxic estrogen quinone formation, in addition to their action via estrogen receptors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-64. doi:1538-7445.AM2012-LB-64