Ovarian cancer is the fifth most commonly diagnosed cancer among women and the most frequent cause of death from gynecologic malignancies in the United States. Molecular mechanisms that initiate and support ovarian tumorigenesis are not well defined. We cloned a novel oncogene """"""""PTTG"""""""" also known as securin from human testis and ovarian tumors and studied its function in tumorigenesis. PTTG is a multifunctional protein and is highly expressed in many tumors, including tumors of ovary. Introduction of PTTG into NIH3T3 and HEK293 cells induces cellular transformation and promotes tumor formation in nude mice, suggesting its strong oncogenic function. Notably, PTTG has been shown to inhibit separation of sister chromatids, and to increase the synthesis and secretion of bFGF, VEGF, and IL-8 as well as activate the expression of the oncogene, c-myc and PI3K/AKT signaling pathway, suggesting that the oncogenic activity of PTTG may involve induction of aneuploidy and chromosomal instability, increased angiogenesis, and production of growth promoting oncogene products. Down-regulation of PTTG expression in ovarian tumor cells in vitro and its deletion in animals (Knockout) results in reduction of tumor development, suggesting its important role in maintenance of cancer phenotype. The long-term objectives of this application are to understand the role of PTTG in ovarian tumorigenesis and validate PTTG as a molecular target for the development of anti- neoplastic agents. In this application we propose: i) to determine the effect of overexpression of PTTG in ovarian epithelial cells on cellular transformation and tumor development in nude mice; ii) to determine the effect of overexpression of PTTG in ovarian surface epithelial cells on ovarian tumor initiation, progression and metastasis in transgenic animals and determine mechanisms that support tumor growth and metastasis; and iii) to determine the effect of down-regulation of PTTG expression in ovarian tumor cells on tumor suppression and metastasis and determine mechanisms that lead to suppression of tumor growth and metastasis. These studies will provide critical information regarding the mechanisms of PTTG in ovarian tumorigenesis and metastasis and set up basis for the development of small molecules to inhibit PTTG function as anti-neoplastic agents. In addition transgenic animal model developed from our studies could enhance efforts aimed at developing new methods for detection, prevention, and treatment of ovarian cancer. ? ? ?
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