It is our goal to understand how ovarian cancer develops so that we can use these insights to design ways to prevent the disease, develop more sensitive diagnostic procedures, and find better approaches for treatment. The initial phase of such studies requires identification of the genes involved in initiation and manifestation of the disease. This work is severely hampered by the complex features of ovarian cancer including: (i) The frequent late stage of diagnosis which yields predominately advanced tumors for genetic analysis; (ii) the failure to agree as to whether there is a precursor lesion; and (iii) the apparent differences in causality of familial ovarian cancer and sporadic disease. Therefore, we have developed an in vitro model for ovarian cancer. In this system, rat ovarian surface epithelial cells are subjected to growth stimulation in vitro. This repetitious requirement for growth frequently results in malignant transformation and in other cases results in the development of a partially transformed phenotype. The transformed cells and the tumors they produce in syngeneic and xenogeneic hosts have many features characteristic of clinical ovarian cancer. Furthermore, the multiple individual transformants allows the frequency of occurrence of change in expression of individual genes to be determined. This provides an indirect suggestion of causality and hence a basis for the selection of candidates for more detailed analysis. Thus, this model is an ideal starting point for efforts to find the genetic basis for ovarian cancer. We have used this system with RNA differential display to identify a candidate ovarian cancer gene. This gene is tentatively named LOT1 (Lost on transformation 1) based on its lost or decreased expression in five of eight malignantly transformed rat ovarian surface epithelial cell lines. The gene is the template for a 6.4kb mRNA and the sequence of a partial cDNA clone is not related to known genes. In the present application, we propose to: (l) complete the cloning of the cDNA for LOT1, (2) fully develop our effort to identify other genes involved in ovarian cancer, and (3) determine the function of LOT1, and initiate functional studies on other genes which show altered expression at high frequency in transformed ovarian surface epithelial cells. We hypothesize that the results generated as this study progresses will increase our understanding of how clinical ovarian cancer develops.
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| Cvetkovic, Dusica; Pisarcik, Debra; Lee, Chan et al. (2004) Altered expression and loss of heterozygosity of the LOT1 gene in ovarian cancer. Gynecol Oncol 95:449-55 |
| Nikitin, Alexander Y; Connolly, Denise C; Hamilton, Thomas C (2004) Pathology of Ovarian Neoplasms in Genetically Modified Mice. Comp Med 54:26-8 |
| Connolly, Denise C; Bao, Rudi; Nikitin, Alexander Yu et al. (2003) Female mice chimeric for expression of the simian virus 40 TAg under control of the MISIIR promoter develop epithelial ovarian cancer. Cancer Res 63:1389-97 |
| Abdollahi, Abbas; Gruver, Briana N; Patriotis, Christos et al. (2003) Identification of epidermal growth factor-responsive genes in normal rat ovarian surface epithelial cells. Biochem Biophys Res Commun 307:188-97 |
| Hamilton, T C; Connolly, D C; Nikitin, A Y et al. (2003) Translational research in ovarian cancer: a must. Int J Gynecol Cancer 13 Suppl 2:220-30 |
| Abdollahi, Abbas; Pisarcik, Debra; Roberts, David et al. (2003) LOT1 (PLAGL1/ZAC1), the candidate tumor suppressor gene at chromosome 6q24-25, is epigenetically regulated in cancer. J Biol Chem 278:6041-9 |
| Selvakumaran, Muthu; Pisarcik, Debra A; Bao, Rudi et al. (2003) Enhanced cisplatin cytotoxicity by disturbing the nucleotide excision repair pathway in ovarian cancer cell lines. Cancer Res 63:1311-6 |
| Cvetkovic, Dusica; Williams, Stephen J; Hamilton, Thomas C (2003) Loss of cellular retinol-binding protein 1 gene expression in microdissected human ovarian cancer. Clin Cancer Res 9:1013-20 |
| Bao, Rudi; Selvakumaran, Muthu; Hamilton, Thomas C (2002) Targeted gene therapy of ovarian cancer using an ovarian-specific promoter. Gynecol Oncol 84:228-34 |
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