Estrogen epoxidation as the molecular basis for breast cancer initiation and prevention

F Yu, PhD

University of Illinois College of Medicine at Rockford, Rockford, IL

AIM: We found that 17 -estradiol (E2 ), like many other chemical carcinogens, could be activated by epoxidation resulting in its ability to bind DNA forming DNA adducts both in vitro and in vivo and to inhibit nuclear DNA-dependent RNA synthesis. A hypothesis was proposed suggesting that E2 epoxidation is the underlying mechanism for the initiation of breast cancer [Carcinogenesis, 17, 1957-1961,1996]. Based on these newly discovered insights, a method to screen chemopreventive agents against breast cancer at the initiation is developed. METHODS: This method is to determine whether a chemical agent is able to prevent the formation of E2 epoxide as measured by both the loss of the ability of E2 to inhibit nuclear RNA synthesis and of [3H]labeled E2 to bind to nuclear DNA. Twelve commercial vegetable oils, five unsaturated fatty acids and the antiestrogen tamoxifen were used for this study. RESULTS: 1) Vegetable oils and fatty acids, independent of their mono- or poly-unsaturated content, were all able to prevent the formation of E2 epoxide. 2) Fatty acids, in contrast to vegetable oils, could be activated by epoxidation and inhibit nuclear RNA synthesis. The order of inhibition was palmitoleic acid > oleic acid > linoleic acid > linolenic acid > arachidonic acid. 3) Tamoxifen (TAM) was also able to prevent the formation of E2 epoxide through a competitive epoxidation mechanism. CONCLUSIONS: A method to screen potential chemopreventive agents at the initiation of breast cancer carcinogenesis is presented. The utility of this technique is illustrated in the screening for the preventive potentials of vegetable oils, fatty acids and TAM. We believe that this screening technique will provide a fast and economical way to identify a wide variety of potential chemopreventive agents for further in vivo animal testing.

KEY WORDS: 17-estradiol epoxide, vegetable oils, fatty acids, tamoxifen, RNA synthesis, DNA binding, breast cancer prevention.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Dietary Influences.