A prominent hallmark of malignant solid tumors is disorganization: in normal tissues, epithelial cells are positionally organized along a sheet of basement membrane and in tumors, this positioning control is lost. The epithelial cell-derived cancer cells invade stroma and expand beyond the normal tissue structure, damaging and interfering with the physiological functions of the organs. Genes such as Disabled-1 and Disabled-2 may function in the positioning of cells. The epithelial-expressed Disabled-2 is frequently lost in breast and ovarian tumor cells and is believed to be a tumor suppressor of relevance in ovarian cancer. Thus, inactivation of Disabled-2 is thought to lead to loss of positioning control and contributes to the neoplastic growth of the epithelial cells in ovarian cancer. We used a gene targeted knockout mouse model to examine the function of Disabled-2 in positioning control of epithelial cells. In mice where Disabled-2 is disrupted by an in-frame replacement/insertion of beta-galactosidase (LacZ), disruption of both copies of Disabled-2 gene results in early embryonic lethality, likely due to its requirement in visceral endoderm cell positioning organization. The heterozygous Dab2 mutant mice are predisposed to uterine and ovarian hyperplasia and dysplasia. We propose the following investigations: 1) Determine the role of Disabled-2 and additional molecular events in morphological transformation using the epithelial transition zones of human ovarian tumor tissues; 2) Study the cellular function of Disabled-2 in cultured cells, particularly of its role in endocytosis and cargo targeting, which are essential to establish polarity in vivo;3) Create ovarian-specific conditional Disabled-2 deficient mice to determine if complete Disabled-2 inactivation causes neoplastic phenotype, and the synergy with inactivation of p53 in ovarian cancer development. The goals of the research are to validate the concept that disruption of epithelial structure, including polarity, is a critical component in epithelial neoplastic morphological transformation and to uncover the molecular details in the process of ovarian tumorigenicity. Such studies will lead to a better understanding of cancer etiology and will contribute to public health by providing cancer preventive stratagy and treatment therapy.
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