2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) elicits antiestrogenic responses in rodents and in MCF-7 human breast cancer cells in culture. Moreover, 2,3,7,8-TCDD exhibits anti-tumorigenic properties against estrogen-dependent rat mammary tumors. Based on structure-activity studies, the antiestrogenicity of 2,3,7,8-TCDD is an aryl hydrocarbon (Ah) receptor-mediated process. We have recently discovered and characterized a series of 1,3,6,8-substituted dibenzofurans (typified by 6-methyl-1,3,8- trichlorodibenzofuran, MCDF) which exhibit moderate affinity for the Ah receptor but are weak against (10000 to 100000 times less toxic than TCDD). These compounds constitute a new subclass of non-toxic aryl hydrocarbons which exhibit antiestrogenic activities (eg < 250 times less active than TCDD) and may be useful as potential antitumoregenic agents. This proposal will focus on three interrelated projects utilizing MCF-7 (estrogen responsive) and MDA-MB-231 (estrogen non-responsive) human breast cancer cells in culture. Project 1 will utilize a suite of chemicals including 2,3,7,8-TCDD and selected non-toxic MCDF analogs (with expected antiestrogenic activity) and characterize the antiestrogenicity of these compounds to human breast cancer cells in culture. Tamoxifen, a well characterized non-steroidal antiestrogen, will serve as a positive control for all experiments. Project 2 will focus on the mechanism of action of this suite of aryl hydrocarbons as anitiestrogens and investigate their effects on occupied nuclear estrogen receptor stability and their modulation of growth factors (eg epidermal growth factor, insu(in-like growth factors, 52K protein and transforming growth factor) associated with the growth of human breast cancer cells. The final project will investigate the anti-tumorigenic effects of the halogenated aryl hydrocarbons on mammary cancer in nude athymic transplanted with human breast cancer cells. These studies will, therefore serve to probe the mechanism of action of both toxic and non-toxic halogenated aryl hydrocarbons and determine the utility of the latter group of compounds as potential antitumor agents for estrogen-responsive mammary cancer.
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