Ovarian cancer is an highly metastatic disease; however, the underlying mechanisms that contribute to the metastatic phenotype are not well understood. A role for the epidermal growth factor receptor (EGFR) in ovarian cancer is suggested by frequent overexpression of this receptor in human tumors. Our preliminary findings indicate that EGFR regulates metastasis-associated cellular functions such as changes in cell adhesive properties, enhanced cell migratory capacity and expression of extracellular matrix degrading proteases in ovarian tumor cell lines. Recently, a mutant EGFR that was originally identified in glioblastoma has been detected at high frequency in tumors of the breast, prostate, ovarian and others. This EGFR mutation is an in frame deletion between nucleotides 275 to 1075 (exons 2-7) of the normal EGFR cDNA sequence giving rise to a receptor that is constitutively active in the absence of ligand. Most frequently designated EGFRvIII, this represents the most prevalent EGFR mutation found in human cancers and it has not been detected in any normal tissues surveyed to date. Despite clinical evidence that EGFRvIII is expressed in a variety of aggressive human tumors including those of the ovary, nothing is known about how this receptor may be involved in ovarian cancer etiology. Our hypothesis is that expression of EGFRvIII in ovarian tumors leads to constitutive activation of key signaling mechanisms that consequently contribute to development of a metastatic phenotype. Our preliminary findings indicate that stable introduction of EGFRvIII into an ovarian tumor cell line alters cellular phenotype with regard to loss of cell:cell contact, increased migration and causes a striking elevation of MMP-9 production with cell-surface localization of this proteinase. To date, studies on EGFRvIII have focused primarily on cell growth regulation by this mutant receptor. Currently, the specific cellular consequences of EGFRvIII expression in ovarian cancer, or the potential contribution of this receptor to ovarian tumor dissemination are unknown. The goals of this proposal are to: 1) determine the functional impact of EGFRvIII expression in ovarian tumor cells in vitro and in vivo with an emphasis on responses associated with tumor dissemination, 2) identify EGFRvIII-mediated signaling mechanisms that are required for the observed phenotype, 3) analyze the enzymatic and functional parameters of cell bound vs solution phase MMP-9, and 4) directly test the impact of cell surface-associated MMP-9 in vitro and in vivo. The proposed studies will address important gaps in our understanding of the impact of activated EGFR in the etioology of ovarian cancer.
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