Ovarian carcinoma (OvCa) is a major cause of cancer- associated morbidity and mortality for women, yet much remains to be learned about its pathogenesis. Like other cancers, OvCas are thought to arise through a multi-step process in which repeated cycles of somatic mutation and clonal selection produce variant progeny with increasingly aggressive growth properties. The genes mutated in cancer frequently encode proteins that function in conserved signaling pathways. Molecular genetic analyses suggest that the different histologic subtypes of OvCa (e.g., serous, clear cell, mucinous, and endometrioid) may represent distinct disease entities and that OvCa precursor lesions may be subtype specific. Hence, a clearer understanding of OvCa pathogenesis might be more readily attained by focusing molecular genetic studies on distinct OvCa types for defects in cell signaling pathways. The ovarian endometrioid adenocarcinomas (OEAs) share a number of molecular genetic features with uterine endometrioid adenocarcinomas, including frequent mutations of the CTNNB1 gene which encodes beta-catenin (beta-cat), a critical component of the highly conserved Wnt signaling pathway. Previous studies suggest that although the Wnt/beta-cat/Tcf pathway may be defective in a substantial percentage of OEAs, it is only rarely altered in other histologic subtypes of OvCa. This application describes studies that are focused on defining the molecular mechanisms by which Wnt pathway defects contribute to the development and behavior of a specific type of OvCa, namely endometrioid adenocarcinomas. Toward this end, four specific aims are proposed: 1) To complete a comprehensive mutational analysis of genes encoding proteins known to regulate the Wnt/beta-cat/Tcf signaling pathway in a large group of primary OEAs; 2) To characterize expression of candidate downstream genes transcriptionally activated by the beta-cat/Tcf signaling pathway in OEAs with known pathway defects; 3) To examine a spectrum of endometriosis lesions (putative OEA precursors) for defects in beta-cat/Tcf pathway genes, and to determine whether expression of mutant beta-cat results in malignant transformation of immortalized cells derived from endometriosis, and 4) To determine if selected beta-cat/Tcf- activated genes are necessary and/or sufficient for neoplastic transformation by mutant beta-cat in RK3E cells or human cells with relevance to ovarian cancer (immortalized ovarian surface epithelial cells expressing telomerase, or cell lines derived from endometriosis).
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