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Modeling Human Epithelial Ovarian Cancer in Mice by Alteration of Expression of the BRCA1 and/or p53 Genes

Principal Investigator: CONNOLLY, DENISE
Institution Receiving Award: FOX CHASE CANCER CENTER
Program: OCRP
Proposal Number: OC030080
Award Number: W81XWH-04-1-0063
Funding Mechanism: New Investigator Award
Partnering Awards:
Award Amount: $508,621.00


PUBLIC ABSTRACT

More than 90% of ovarian tumors are epithelial ovarian cancers making them the most common form of the disease. When diagnosed at the early stage, the chances of curing the disease are good. Most cases, however, are diagnosed at the advanced stage, reducing the overall 5-year survival rate to only 20 out of every 100 patients.

The epithelial ovarian cancers have been intensely studied. Unfortunately, the underlying causes of the disease, especially its initiation and early progression, have been difficult to define for two reasons. First, most patients are diagnosed when the disease is at an advanced stage when many aspects of normal cellular growth control have failed. Second, the lack of adequate animal models of epithelial ovarian cancer has delayed advances in research directed toward understanding the causes of disease and developing strategies for detection, prevention, and treatment.

About one out of every 19 cases of epithelial ovarian cancer is inherited. Unlike nonhereditary (sporadic) ovarian cancer, some of the underlying genetic causes of hereditary ovarian cancer are well understood. The majority, >90%, of inherited cases are the result of inherited mutations in the breast cancer associated gene 1 (BRCA1). This gene was originally identified based on genetic linkage to families with an increased risk of developing breast and ovarian cancer. It is involved in controlling normal cellular growth and is thought to suppress the growth of tumors. That is, if BRCA1 is mutated, the risk to develop breast and ovarian cancer increases. Another gene that is important in the development of cancer is the p53 gene. It also helps maintain normal cellular growth and is the most commonly mutated gene in all human cancers. It has been shown to be mutated in at least 50% of all cases of epithelial ovarian cancer. In addition to mutations of BRCA1, mutations of the p53 gene are often found in patients with breast and ovarian cancer syndrome. Based on the importance of both of these genes in the development of this type of ovarian cancer, we hypothesize that inactivation of BRCA1 and p53 in the ovaries of mice will result in epithelial ovarian cancer in the animals.

The objectives of this proposal are to: (1) develop mouse models of human epithelial ovarian cancer by inactivation of BRCA1 and p53 singly or at the same time in the mouse ovarian surface epithelial cells; (2) investigate whether a difference exists between the complete absence of p53 or the presence of a dominantly acting p53 mutant in ovarian tumorigenesis in mice; and (3) identify genes and cellular pathways, downstream of BRCA1 and p53 inactivation/mutation, that contribute to ovarian carcinogenesis.

This research is likely to result in the establishment of genetically relevant mouse models of inherited epithelial ovarian cancer as well as provide important insights into the development and progression of sporadic cases of this disease. This will allow us to learn more about other genes and cellular pathways that contribute to the development and progression of human ovarian cancer. In addition, we predict that we will identify a spectrum of disease from early benign and invasive lesions to late stage invasive lesions, providing valuable tools for identifying and evaluating detection, prevention, and treatment strategies that may help more patients survive ovarian cancer.