description) Uterine leiomyomas (fibroids) are the most frequent gynecologic neoplasm in women. The potential impact of environmental estrogens on the development of these estrogen-responsive tumors is virtually unknown. Female Eker rats exhibit a unique susceptibility to the development of uterine leiomyomas due to a germline tumor suppressor gene mutation. The principal investigator's laboratory has developed an in vitro/in vivo model system using these rats for studying the hormonal responsiveness of leiomyomas. The estrogen receptor contains two transactivation domains, TAF 1 and TAF 2, which determine the activity of the liganded receptor. Preliminary data from the principal investigator's laboratory and others suggest that compounds that act as agonists in the myometrium (17-beta-estradiol and diethylstilbestrol (DES)) activate TAF 2, whereas tamoxifen (TAM), which is an estrogen receptor antagonist in the myometrium, inactivates TAF 2 function. The working hypothesis is that activation of TAF 2 function by environmental estrogens is a determinant of their ability to act as agonists in the myometrium and promote the growth of these estrogen-dependent tumors.
The specific aims outlined in this proposal are designed to test this hypothesis by establishing that leiomyomas can be induced in Eker rats by exogenous estrogens, characterizing the ability of environmental estrogens to activate TAF 1 and TAF 2 functions of the estrogen receptor in a myometrial cell background and correlating TAF 2 activation by these compounds in vitro with their ability to induce leiomyomas in vivo in female Eker rats. These experiments may yield new insights into the mechanism of action of environmental estrogens and facilitate the development of in vitro assays predictive of the activity of exogenous estrogens in vivo.
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