A proposed mechanism of tamoxifen in breast cancer prevention.
Recent clinical trials suggest that tamoxifen (TAM) is a preventive agent for breast cancer, however, the mechanism is unknown. Previously, we found that both 17beta-estradiol (E2) and estrone (E1) could be activated by epoxidation resulting in their ability to bind to DNA, forming DNA adducts both in vitro and in vivo, and to inhibit nuclear DNA-dependent RNA synthesis. Since epoxidation is required for the activation of many well-known chemical carcinogens including benzo(a)pyrene, 7,12-dimethylbenz(a)anthracene, aflatoxins, etc., we proposed that estrogen epoxidation is the underlying mechanism for the initiation of breast cancer (Carcinogenesis 17 (1996) 1957). Here, we report that TAM is able to dramatically inhibit the formation of E2 and E1 epoxides as measured by both the loss of their ability to inhibit nuclear DNA-dependent RNA synthesis and to bind to nuclear DNA. These findings suggest that the breast cancer preventive effect of TAM may be through a competitive epoxidation inhibition mechanism that prevents the formation of E2 and E1 epoxides and consequently, the initiation of breast cancer.
Yu
Fu-Li
FL
Department of Biomedical Sciences, University of Illinois, College of Medicine at Rockford, 1601 Parkview Avenue, Rockford, IL 61107, USA. fuliyu@uic.edu
Bender
Wanda
W
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000517:prevention & control*; D018736:DNA Adducts; D004852:Epoxy Compounds / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism*; D004970:Estrone / Q000378:metabolism*; D005260:Female; D006801:Humans; D008099:Liver; D012313:RNA / Q000096:biosynthesis; D051381:Rats; D013629:Tamoxifen / Q000494:pharmacology*
D016588:Anticarcinogenic Agents; D018736:DNA Adducts; D004852:Epoxy Compounds; D013629:Tamoxifen; D004970:Estrone; D004958:Estradiol; D012313:RNA