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    Molecular Mechanism of Estrogen Antagonists induced Suppression of Breast Cancer

    Scientific Abstract:
    Title: Molecular Mechanism of Estrogen Antagonists induced Suppression of Breast Cancer Background: Estrogen antagonists are widely employed in the treatment of breast cancer. They also comprise the most promising drugs for breast cancer chemo-prevention. Despite these facts, the molecular mechanisms by which these compounds inhibiting cellular proliferation are not fully defined. One of such compound, tamoxifen, leads to highly-significant decreases in the rates of both disease recurrence and death, but tamoxifen is limited by a less that 50% response rate in breast cancer prevention and the inevitable development of cellular resistance in breast cancer therapy. Our preliminary studies have demonstrated that depletion of prohibitin protein or introducing dominant negative forms of co-repressors of prohibitin overcomes 4-hydroxytamoxifen-induced growth suppression in breast cancer cells. A potential role for prohibitin gene in breast cancer has also been suggested in earlier studies, in which prohibitin was found to be mutated in some sporadic breast cancers. Recent report indicate that JNK is activated by tamoxifen and our preliminary studies have found that introducing a dominant negative JNK1 can block the effect of extrogen antagonists, suggesting the possible involvement of the JNK1 pathway in estrogen antagonist-induced growth suppression. Objective/Hypothesis: I hypothesize that prohibitin and its co-repressors Brg-1/Brm play a role in estrogen antagonists-induced growth suppression of breast cancer, and that estrogen antagonists target the prohibitin/E2F pathway via JNK to affect breast cancer cell proliferation. The studies proposed will test and prove a critical and necessary role for prohibitin/Brm-Brg/E2F axis in the response of breast cancer cells to estrogen antagonists. Specific Aims: I. Determine the molecular mechanism of estrogen antagonist-induced growth suppression. II. Determine the mechanism of E2F regulation by estrogen antagonist. III. Determine the mechanism of signal transduction of estrogen antagonist-induced growth repression of breast cancer cells Study Design: Northern blot or RT-PCR and immunoblot analysis will be carried out to assess the regulation of endogenous E2F-responsive promoters by estrogen antagonists. The requirement for prohibitin/Brg-1/Brm in estrogen antagonist-mediated transcriptional repression of natural E2F-responsive promoters will be tested, using anti-sense and dominant-negative strategies. Chromatin immuno-precipitation assays (CHIP) will be employed to study the effect of estrogen antagonists on the interactions of prohibitin, Brg-1, and Brm with the natural E2F-responsive promoters. Dominant negative strategies, Kinase assays, CHIP assays, IP-western blots, and EMSA will be employed to assess the involvement/requirement of the JNK pathway in estrogen antagonist-induced growth suppression. Potential Outcomes and Benefit of the Research: A major problem facing breast cancer chemo-prevention is the low response rate. Estrogen antagonist treatment is further limited by the inevitable development of resistance. The lack of information about the molecular mechanisms of estrogen antagonists-mediated growth suppression prevents the development of strategies to overcome these problems. Our demonstration of the involvement of prohibitin in antagonist induced growth arrest suggests that the prohibitin/E2F pathway is the/a cellular target for estrogen antagonists, and thereby also implicates prohibitin as a potentially important target for breast cancer therapy. These studies will elucidate the molecular mechanism of anti-cancer effect of estrogen antagonist.

    Lay Abstract:
    Title: Molecular Mechanism of Estrogen Antagonists induced Suppression of Breast Cancer A group of anticancer drugs, called estrogen antagonists, like tamoxifen, are important in the treatment of breast cancer. A major problem facing this treatment is the development of resistant to the drug. Improved drugs are needed to conquer this problem. However, the lack of information about how estrogen antagonists mediate growth suppression of breast cancer cells prevents improved drug design. One powerful method for developing new treatment strategies for breast cancer is to study the genes involved in the development of this disease and alter their function. One example is the cancer-preventing gene prohibitin, which has been found to be mutated in this disease. In the search for targets of tamoxifen in breast cells, we found that the product of prohibitin gene, prohibitin protein, mediates the anti-cancer effect of this drug. This finding suggests that prohibitin is important in breast cancer. Based on the literature and our results, we propose to discover the exact role of prohibitin in breast cancer development and in breast cancer treatment by estrogen antagonists. We have recently discovered and reported one major mechanism underlying prohibitin’s ability to regulated cell cycle genes and the findings is published in the prestigious EMBO J [Vol. 21(12):1-10]. All the techniques required for the study are well established in our lab. The information generated in this study will dramatically facilitate the design of new drug for breast cancer, which will overcome the problem of drug resistance.