In the proposed studies, we will examine the regulation of Stat3 (Signal transducer and activator of transcription 3) by p53 in breast and ovarian cancer cells expressing constitutively active Stat3. Constitutively active Stat3 may play a important role of oncogenic transformation of normal cells to malignant cells and may inhibit apoptosis. Recent studies suggest that constitutively Stat3 signaling contribute to oncogenesis by stimulating cell proliferation, promoting tumor angiogenesis, and preventing apoptosis. Constitutive activation of Stat3 has been frequently detected in a variety of cancer samples and cancer cell lines. These studies suggest that constitutively activated Stat3 plays a role on the human cancer carcinogenesis. Mutation of the p53 tumor suppressor is one of the most commonly detected genetic alterations in human cancer. Our preliminary studies demonstrated that expression of wild-type (wt) p53 but not mutant p53 significantly reduced phosphorylated or active form of Stat3 in breast, ovarian and prostate cancer cells that express constitutively active Stat3. Wt p53 also induced dramatic apoptosis in these cancer cell lines. We hypothesize that the anti-proliferative activities of wt p53 are not compatible with the constitutive activation of Stat3 in cancer cells. Constitutive activation of Stat3 by upstream activator(s) may activate p53 activities to induce growth arrest/apoptosis of cells. Activated p53 may induce a p53 downstream target that inhibits Stat3 in a negative feed back manner. p53 may then serve a safeguard against oncogenic deregulation of Stat3. Only cancer cells that further mutate p53 or inactivate p53 pathway may be able to escape p53-dependent apoptosis/growth arrest and be able to continue tumor progression. Therefore, constitutive activation of Stat3 may be selectively present in cancer cells that have harbored inactivating mutation or deletion of the p53 gene. This is a testable hypothesis and this hypothesis is partially supported by our survey from the published reports of the status of Stat3 and p53 in a panel of human cancer cell lines. We found that all breast, ovarian and prostate cancer cell lines that express constitutively active Stat3 only express mutant or null p53. In this proposal, we seek to examine the functional regulation of two potentially important genes that frequently altered in breast and ovarian cancers, Stat3 and p53. The following specific aims will be studied to address these questions: 1. Examine the molecular mechanism by which p53 inhibits Stat3 in cancer cells expressing constitutively active Stat3. 2. Examine whether the transcription activity of p53 is necessary to inhibit Stat3. 3. Evaluate whether down regulation of constitutively active Stat3 is associated with apoptosis induced by p53. 4. Examine whether constitutive activation of Stat3 selectively occurs in breast and ovarian cancer cell lines and cancer specimens containing p53 mutations or deletions.
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