Like other cancers, ovarian carcinomas are thought to arise through a multi-step process in which clonal selection acts on cells with somatic mutations and altered gene expression to allow outgrowth of variant progeny with increasingly aggressive growth properties. The genes mutated in cancer frequently encode proteins that function in conserved signaling pathways. One subtype of ovarian carcinoma, namely ovarian endometrioid adenocarcinoma (OEA), is characterized by frequent defects in the Wnt/?-cat/Tcf signaling pathway (i.e., mutations in the CTNNB1, APC, AXIN1 orAXIN2 genes). We have shown the status of this pathway is a major determinant of global gene expression in OEAs. Through comparison of gene expression in pathway-intact versus pathway-deregulated tumors, we have identified several ? -cat/Tcf activated genes likely to play important roles in OEA pathogenesis. Activation of K-Ras and inactivation of Pten in the ovarian surface epithelium of mice leads to carcinomas with histopathologic features similar to human OEAs. But, in human OEAs with PI3K/Pten/Akt pathway defects, K-Ras mutations are not often seen. We have now acquired data suggesting Wnt/ ? -cat/Tcf and PI3K/Pten/Akt signaling pathway defects likely cooperate in OEA pathogenesis. Specifically, human OEAs with Wnt/ ? -cat/Tcf pathway defects often harbor mutations that deregulate PI3K/Pten/Akt signaling. This application describes efforts to define the molecular mechanisms by which defects in these two pathways contribute to the pathogenesis and clinical behavior of OEAs, including work to develop and analyze murine models of OEA that recapitulate the signaling pathway defects observed in human tumors. Toward this end, four aims are proposed: 1) To continue efforts to identify and characterize ?-cat/Tcf regulated genes important in OEA pathogenesis; 2) To complete a comprehensive mutational analysis of genes encoding proteins known to regulate PI3K/Pten/Akt signaling in OEAs, and to define a gene expression signature associated with defects in this signaling pathway; 3) To define and characterize key downstream transcriptional target genes linked to deregulated PI3K/Pten/Akt signaling in OEA pathogenesis; and 4) To continue efforts to characterize mouse models of OEA, including a new model based on conditional deregulation of Wnt/ ?-cat/Tcf and PI3K/Pten/Akt signaling in the ovarian surface epithelium. Relevance: Our studies will enhance our understanding of the molecular basis underlying a particular type of ovarian cancer, and will allow us to develop and characterize mouse models of ovarian cancer likely to be of greatest utility for testing novel therapeutics that target specific cell signaling pathways. ? ? ?
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