An interactive, interdisciplinary group will focus on the pathobiology of ovarian cancer at the genetic, molecular, cellular, and whole organism levels. 1) The first project will employ genome copy number and expression profiling by array CGH and expression array analysis to detect and localize recurrent genome copy number or gene expression changes and their association with histology, progression and clinical outcome; associations will be validated with tissue microarrays and 2) gene discovery using high-resolution array CGH to detect regions of recurrent genomic changes, comparative genomic sequencing to identify genes associated with narrowly defined regions, and analyzing functions of genes present at altered genome copy number and differentially expressed in human tumors. In the second project, based on the hypothesis that understanding mechanisms underlying production and action of LPA will improve understanding of tumorigenesis progression, and outcome and will lead to new diagnostic and therapeutic approaches, the role of LPA and its receptors in carcinogenesis will be characterized, the genes induced by LPA in ovarian cancer cells identified, and the possible use of LPA levels in detection and management assessed. The third project, based on the discovery of a putative novel tumor suppressor gene, ARHI, the clinical significance and mechanism of loss of ARHI expression in malignant ovarian epithelial cells, will be studied by determining: 1) effects of ARHI expression of proliferation, invasion, metastasis and survival of ovarian cancer cells, 2) mechanisms by which ARHI interferes with signal transduction; and 3) use of ARHI for gene therapy of ovarian cancer xenografts with our without cytotoxic drugs. In the fourth project, because of an increased copy number in PI3-K in 80% of ovarian cancers, the role of abnormalities in the PI3K pathway in pathogenesis, the effect of abnormalities in the PI3-K pathway on responsiveness to growth factors and, the mechanisms regulating signaling through the PI3-K cascade in ovarian cancer cells will be determined. The projects will be subserved by three cores: Administration, Biometry and Tissue/Pathology.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA064602-05A1
Application #
6266791
Study Section
Subcommittee G - Education (NCI)
Program Officer
Mohla, Suresh
Project Start
1996-04-15
Project End
2006-01-31
Budget Start
2001-04-25
Budget End
2002-01-31
Support Year
5
Fiscal Year
2001
Total Cost
$2,068,795
Indirect Cost
Name
University of California San Francisco
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Lu, Z; Yang, H; Sutton, M N et al. (2014) ARHI (DIRAS3) induces autophagy in ovarian cancer cells by downregulating the epidermal growth factor receptor, inhibiting PI3K and Ras/MAP signaling and activating the FOXo3a-mediated induction of Rab7. Cell Death Differ 21:1275-89
Cheng, Kwai Wa; Agarwal, Roshan; Mitra, Shreya et al. (2012) Rab25 increases cellular ATP and glycogen stores protecting cancer cells from bioenergetic stress. EMBO Mol Med 4:125-41
Badgwell, D B; Lu, Z; Le, K et al. (2012) The tumor-suppressor gene ARHI (DIRAS3) suppresses ovarian cancer cell migration through inhibition of the Stat3 and FAK/Rho signaling pathways. Oncogene 31:68-79
Zou, Chun-Fang; Jia, Luoqi; Jin, Hongyan et al. (2011) Re-expression of ARHI (DIRAS3) induces autophagy in breast cancer cells and enhances the inhibitory effect of paclitaxel. BMC Cancer 11:22
Cheong, Jae-Ho; Park, Eun Sung; Liang, Jiyong et al. (2011) Dual inhibition of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinical cancer models. Mol Cancer Ther 10:2350-62
Agarwal, Roshan; Carey, Mark; Hennessy, Bryan et al. (2010) PI3K pathway-directed therapeutic strategies in cancer. Curr Opin Investig Drugs 11:615-28
Ishida, Seiko; McCormick, Frank; Smith-McCune, Karen et al. (2010) Enhancing tumor-specific uptake of the anticancer drug cisplatin with a copper chelator. Cancer Cell 17:574-83
Short, John D; Dere, Ruhee; Houston, Kevin D et al. (2010) AMPK-mediated phosphorylation of murine p27 at T197 promotes binding of 14-3-3 proteins and increases p27 stability. Mol Carcinog 49:429-39
Liu, Shuying; Murph, Mandi; Panupinthu, Nattapon et al. (2009) ATX-LPA receptor axis in inflammation and cancer. Cell Cycle 8:3695-701
Huang, Shaoyi; Chang, In Soon; Lin, Wenbo et al. (2009) ARHI (DIRAS3), an imprinted tumour suppressor gene, binds to importins and blocks nuclear import of cargo proteins. Biosci Rep 30:159-68

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