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 percent 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. 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 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 mechanism of estrogen antagonist-induced growth repression of breast cancer cells II. Determine the molecular level at which estrogen antagonists regulate prohibitin activity. 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. Relevance: A major problem facing breast cancer chemo-prevention is the low response rate. Estrogen antagonists 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 the problems. Our demonstration of the involvement of prohibitin in 4-HT 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.
| (2011) Retraction. Requirement for chromatin-remodeling complex in novel tumor suppressor HIC1-mediated transcriptional repression and growth control. Oncogene 30:4374 |
| Zhang, Baohua; Faller, Douglas V; Wang, Sheng (2009) HIC1 regulates tumor cell responses to endocrine therapies. Mol Endocrinol 23:2075-85 |
| Zhang, B; Chambers, K J; Leprince, D et al. (2009) Requirement for chromatin-remodeling complex in novel tumor suppressor HIC1-mediated transcriptional repression and growth control. Oncogene 28:651-61 |
| Zhang, B; Chambers, K J; Faller, D V et al. (2007) Reprogramming of the SWI/SNF complex for co-activation or co-repression in prohibitin-mediated estrogen receptor regulation. Oncogene 26:7153-7 |
| Wang, Sheng; Zhang, Baohua; Faller, Douglas V (2004) BRG1/BRM and prohibitin are required for growth suppression by estrogen antagonists. EMBO J 23:2293-303 |
