Our preliminary results suggest that deletion of other tumor suppressor genes, such as (S.O., unpublished). is the precursor tissue for these ovarian carcinomas, and that introduction of oncogenes causes phenotypic changes in the ovarian surface epithelial cells. The induced ovarian tumors in mice resembled human ovarian carcinomas in their rapid progression and intraperitoneal metastatic spread. Introduction Ovarian carcinoma is the fifth most common cause of cancer among women in the United States, with more than 23,000 new cases diagnosed and approximately 14,000 deaths each year (Greenlee et al., 2000). When diagnosed at an early stage, ovarian carcinoma has a survival rate approaching 90%. However, due to the asymptomatic nature of early stages of the disease, more than two-thirds of cases are not diagnosed until the disease has spread beyond the ovaries. For these patients, the five-year survival rate is significantly lower. Despite recent advances in cytoreductive surgery and combination chemotherapy, improvement in long-term survival for ovarian cancer patients has been slight. The causes of ovarian carcinoma are IL6 antibody not known, although the majority of evidence suggests that reproductive factors and heredity may play roles in the origin of this disease (Holschneider and Berek, 2000). Studies of human ovarian cancer specimens have revealed several types of genetic alterations. Mutation of the tumor suppressor gene is the most frequently identified genetic alteration in serous and poorly differentiated epithelial ovarian carcinomas, affecting more than 50% of advanced and early-stage carcinomas (reviewed in Aunoble et al., 2000). Proto-oncogenes such as chas been reported in approximately 30% of ovarian tumors (Baker et al., 1990; Wang et al., 1999). Point mutations at codon 12 of the Kgene have been detected in 30%C50% of mucinous adenocarcinomas and tumors of low malignant potential, and in 10%C20% of serous adenocarcinomas (Mok et al., 1993; Teneriello et al., 1993; Cuatrecasas et al., 1997; Caduff et al., 1999; Dokianakis et al., 1999; Morita et al., 2000; Suzuki et al., 2000). Activation of the phosphatidylinositol 3-kinase (PI3-kinase)/Akt pathway has been detected in several ovarian cancer cell lines and in approximately 30% of ovarian cancer specimens (Cheng et al., 1992; Bellacosa Lincomycin Hydrochloride Monohydrate et al., 1995; Shayesteh et al., 1999; Yuan et al., 2000; Sun et al., 2001). Most of the evidence that these oncogenes and tumor suppressor genes are involved in ovarian carcinogenesis is based on immunohistological examination of tumors. However, the molecular mechanisms by which these genes contribute to initiation and development of ovarian cancer are still poorly understood. SIGNIFICANCE The study of ovarian carcinogenesis has been limited by the lack of appropriate tumor models. We have developed and characterized a mouse model system for recapitulating human ovarian carcinoma development and progression. The system was designed to be used for the evaluation of multiple genetic lesions, individually and in combination. We have demonstrated that combinations of genetic lesions that are commonly present in human ovarian carcinomas can induce ovarian carcinomas in mouse ovarian cells. Our findings support the theory that the ovarian surface epithelium is the precursor tissue for ovarian carcinomas. We expect that this model will be useful for studying the basic biology of ovarian carcinoma initiation and progression, identifying markers of ovarian tumor progression, and establishing parameters for distinguishing a variety of biological behaviors such as metastatic ability, invasiveness, and sensitivity of ovarian tumors to different therapeutic interventions that target specific molecular pathways altered in ovarian carcinoma. Advancement in understanding the initiation and progression of ovarian carcinoma has been slow, mainly due to the lack of an appropriate experimental model. Even Lincomycin Hydrochloride Monohydrate the tissue of origin in ovarian cancer is not completely understood. Most human ovarian carcinomas are thought to arise from the ovarian surface epithelium (reviewed in Feeley and Wells, 2001). However, it is difficult to explain the diversity of ovarian carcinomas that arise from this relatively homogenous tissue. Very little is known about cellular phenotypic changes in the ovarian surface epithelium as it becomes cancerous or metastatic (Auersperg et al., 2001). Despite its clinical importance, the biology of this tissue is Lincomycin Hydrochloride Monohydrate poorly understood, and evidence for its role in ovarian carcinogenesis is based almost entirely on morphologic and histologic examination of clinical tumor specimens and immortalized ovarian cancer cell lines. The direct progression of benign ovarian lesions to clinical carcinoma has not been clearly demonstrated for ovarian cancer (reviewed in Feeley and Wells, 2001). Since early stage malignancy is infrequently detected in patients, the morphologic and genetic changes that occur as the benign epithelium becomes malignant are not well defined. At present, there is little evidence for a genetic model of multi-step tumor progression in ovarian cancer, and there is speculation that ovarian carcinoma occurs de novo, without any intermediate precursor lesion (Bell and Scully, 1994). A suitable animal model, in which.