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).

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-ET-1 (01))
Program Officer
Yassin, Rihab R,
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
Zip Code
Karnezis, Anthony N; Cho, Kathleen R (2017) Preclinical Models of Ovarian Cancer: Pathogenesis, Problems, and Implications for Prevention. Clin Obstet Gynecol 60:789-800
Zhai, Yali; Kuick, Rork; Tipton, Courtney et al. (2016) Arid1a inactivation in an Apc- and Pten-defective mouse ovarian cancer model enhances epithelial differentiation and prolongs survival. J Pathol 238:21-30
Wu, Rong; Baker, Suzanne J; Hu, Tom C et al. (2013) Type I to type II ovarian carcinoma progression: mutant Trp53 or Pik3ca confers a more aggressive tumor phenotype in a mouse model of ovarian cancer. Am J Pathol 182:1391-9
Wang, Hanxiao; Galbán, Stefanie; Wu, Rong et al. (2013) Molecular imaging reveals a role for AKT in resistance to cisplatin for ovarian endometrioid adenocarcinoma. Clin Cancer Res 19:158-69
Wu, Rong; Hu, Tom C; Rehemtulla, Alnawaz et al. (2011) Preclinical testing of PI3K/AKT/mTOR signaling inhibitors in a mouse model of ovarian endometrioid adenocarcinoma. Clin Cancer Res 17:7359-72
Zhai, Y; Iura, A; Yeasmin, S et al. (2011) MSX2 is an oncogenic downstream target of activated WNT signaling in ovarian endometrioid adenocarcinoma. Oncogene 30:4152-62
Bommer, Guido T; Feng, Ying; Iura, Ayaka et al. (2010) IRS1 regulation by Wnt/beta-catenin signaling and varied contribution of IRS1 to the neoplastic phenotype. J Biol Chem 285:1928-38
van de Sluis, Bart; Mao, Xicheng; Zhai, Yali et al. (2010) COMMD1 disrupts HIF-1alpha/beta dimerization and inhibits human tumor cell invasion. J Clin Invest 120:2119-30
Cho, Kathleen R (2009) Ovarian cancer update: lessons from morphology, molecules, and mice. Arch Pathol Lab Med 133:1775-81
Cho, Kathleen R; Shih, Ie-Ming (2009) Ovarian cancer. Annu Rev Pathol 4:287-313

Showing the most recent 10 out of 19 publications