Both CD44 and p185HER2 confer the malignant properties of abnormal cell growth, migration and invasion. Furthermore, CD44 forms a complex with p185HER2 and these two molecules closely interact with a number of signaling molecules, thereby activating cytoskeleton function and tumor-specific phenotypes. In this continuation research proposal, we plan to test the hypothesis that CD44-p185HER2 interaction with specific signaling molecules (e g Vav2, Grb2, c-Src kinase and AKT) promotes the concomitant activation of multiple signaling pathways leading to cytoskeleten changes, tumor cell-specific behaviors (e.g. tumor cell growth, survival, invasion and migration) and ovarian cancer progression. To test this hypothesis, we plan to use a variety of biochemical, molecular biological techniques and immunohistochemical staining to elucidate CD44-p185HER2 interaction with the various signaling molecules. We will evaluate the functional ramifications of these interactions with respect to cytoskeleton changes and tumor cell-specific behaviors (e.g. tumor cell growth, survival, migration and invasion). In addition, we plan to analyze the co-expression of CD44v-p185HER2 and various signaling molecules (e.g. Vav2, c-Src and/or AKT) in human ovarian carcinoma tissues obtained from ovarian cancer patients using immunohistochemistry. We will also employ a novel signaling perturbation strategy to impair CD44-p185HER2 interaction with Racl/Ras signaling and c- Src/AKT activation by constructing a number of Vav2/Grb2 and c-Src/AKT dominant negative mutants Finally, we will establish a therapeutic antisense and ribozyme gene therapy procedures to specifically inhibit the mRNA encoding selected CD44 isoforms (and/or p185HER2) in order to effectively block the expression of these CD44 isoforms (and/or p185HER2) involved in Racl/Ras signaling, c-Src/AKT activation and the downstream oncogenic signaling events (e g cytoskeleton changes, tumor cell growth, survival, migration and invasion) These studies may identify useful structure/function-related markers for ovarian cancer detection and prognosis. We believe that the new information obtained from this proposal may establish the CD44-p185HER2 complex and associated signaling molecules as important tumor markers for the early detection and evaluation of oncogenic potential, as well as allow the development of new drug targets to inhibit CD44-p185HER2-mediated ovarian cancer progression.
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