Biochemical pathways involved in ovarian carcinoma are poorly understood, mainly because of the lack of suitable models for the molecular characterization of ovarian carcinoma induction and progression. We developed a mouse model for ovarian carcinoma in which multiple genes can be introduced into mouse ovarian surface epithelial cells and give rise to tumors that largely resemble human ovarian carcinoma. We will use this system to identify additional combinations of genetic lesions that act in concert to induce ovarian carcinoma in mice. Defined sets of genetic lesions that are commonly present in human ovarian carcinomas will be introduced into mouse primary ovarian epithelial cells to determine which combinations of genetic lesions are capable of inducing a tumorigenic state in these cells. This knowledge will be used for the development of genetically defined mouse models in which the tumor phenotype can be correlated to the primary genetic events that trigger tumor formation. We will use expression profiling of genetically defined cell lines to determine whether specific combinations of genetic lesions activate specific biochemical pathways, and to identify downstream targets of genes that induce ovadan cancer. Metastatic tumors and cell lines will be derived from the primary transformed ovarian cell lines. We will then compare expression profiles between primary transformed cell lines and their corresponding metastatic cell lines in order to identify genes that are associated with the process of metastasis. Individual genes that are downregulated in metastatic cells will be re-introduced into these cells to test for their ability to suppress ovarian tumor growth and metastasis. Individual genes that are upregulated in metastatic cells will be introduced into primary cells to test their ability to induce growth and metastatic properties in these cells. We will compare expression profiles between metastatic cell lines with different genetic lesions to determine whether the molecular changes that occur during the metastatic process are universal or dependent upon the initiating genetic events. Activation of individual components of biochemical pathways in the mouse model will be validated by identification of these components in human ovarian carcinomas of different types and metastatic potential. Our expectation is that the knowledge from the molecular biology of ovarian cancer will be translated into improvements in diagnosis and the development of tumor therapy tailored to the causative genetic events in human ovarian cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA103924-04
Application #
7214752
Study Section
Pathology B Study Section (PTHB)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2004-05-01
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
4
Fiscal Year
2007
Total Cost
$305,173
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Wang, Ying; Cheon, Dong-Joo; Lu, Zhen et al. (2008) MUC16 expression during embryogenesis, in adult tissues, and ovarian cancer in the mouse. Differentiation 76:1081-92
Miao, Jiangyong; Wang, Zuncai; Provencher, Heather et al. (2007) HOXB13 promotes ovarian cancer progression. Proc Natl Acad Sci U S A 104:17093-8
Chaudhuri, Devyani; Orsulic, Sandra; Ashok, Badithe T (2007) Antiproliferative activity of sulforaphane in Akt-overexpressing ovarian cancer cells. Mol Cancer Ther 6:334-45
Xing, Deyin; Orsulic, Sandra (2006) A mouse model for the molecular characterization of brca1-associated ovarian carcinoma. Cancer Res 66:8949-53
Sale, Sanja; Orsulic, Sandra (2006) Models of ovarian cancer metastasis: Murine models. Drug Discov Today Dis Models 3:149-154

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