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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA094172-06A1
Application #
7318292
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Yassin, Rihab R,
Project Start
2002-02-01
Project End
2012-05-31
Budget Start
2007-07-30
Budget End
2008-05-31
Support Year
6
Fiscal Year
2007
Total Cost
$261,178
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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

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