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.