The ultimate goals of the research presented in this application are to identify strategies to more effectively prevent, diagnose, and treat ovarian cancer. The hypothesis to be tested is that the identification of the genetic changes responsible for disease initiation and progression will suggest avenues to meet these long term objectives. As an approach to identify genetic changes, an ovarian cancer model was developed using rat ovarian surface epithelial (ROSE) cells. Studies related to this model during the previous funding cycle include: (i) Cloning rLot1 (lost on transformation) and hLOT1, a gene that shows frequently lost or altered expression in transformed ROSE cells and in human ovarian cancer cell lines; (ii) Showing that the gene maps to a frequent site of loss of heterozygosity (LOH) (chromosome 6q25) for many solid tumors including ovarian cancer; (iii) Determining that LOT1 is a nuclear transcription factor regulated by epidermal growth factor and that constitutive over-expression is a negative regulator of ovarian cancer cell growth; (iv) Using the technique of genome scanning to clone cathepsin B gene from a hsr/amplicon present in one of the transformed ROSE cell lines; (v) Developing a modification of suppression subtractive hybridization (SSH) referred to as consolidative SSH (CSSH) and using the method to identify 28 cDNA fragments expressed in normal ROSE cells but not in four independent transformed ROSE cell lines; and (vi) Expanding studies to cancer prone ovaries of humans leading to identification of a preneoplastic phenotype. Our findings of the LOT1 gene's expression and function suggest a clinical relevance and logical directions toward identification of the gene's altered regulatory pathway and the impact on ovarian oncogenesis and/or cancer progression. The general hypothesis to be examined in this proposal is that the transcription factor LOT1 transduces antiproliferative signals and behaves as a tumor/growth suppresser gene regulating other genes which inhibit the malignant phenotype. To elaborate these mechanisms we will investigate the upstream regulators and downstream events associated with the action of the LOT1 protein and to determine how these normal processes are perturbed in ovarian malignancies. These endeavors are set forth in the following Specific Aims:
SPECIFIC AIM number l. Determine the basis for altered presence or function of LOT1 in ovarian cancer.
SPECIFIC AIM number 2. Analyze the molecular mechanisms utilized by normal and malignant ovarian surface epithelial cells to down-regulate LOT1 expression.
SPECIFIC AIM number 3. Analyze the role of LOT1 as a DNA binding protein with transcriptional regulatory activity.
SPECIFIC AIM number 4. Identify proteins which interact with LOT1.
| 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 |
| Galvez, Jose J; Cardiff, Robert D; Munn, Robert J et al. (2004) Mouse models of human cancers (Part 2). Comp Med 54:13-5 |
| 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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