EXCEED THE SPACEPROVIDED.Ovarian cancer is the leadingcause of death among gynecologic cancers in the United States. The prostaglandin (PG)pathway mediated by cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes is implicated in ovulationand has been suggested as a potential factor in the etiology of ovarian cancer. Preliminary Data: We have utilizedcDNA microarrays to compare normal ovarian tissue samples to ovarian carcinomas, and through this process haveshown expression levels of COX-1 to be more than 2-fold higher in the cancers. Data published by our collaboratorssimilarly demonstrates that COX-1, not COX-2, is highly expressed in ovarian malignancies. Hypothesis and Aims:The long-range goal of this research is to determine the specific contributions of COX-1 to ovarian carcinogenesis. Wehypothesize that in ovarian cancers, COX-1 induces PGE2 production, which targets phosphatidylinositol3kinase/protein kinase B (PI3K/AKT) signaling and components of this pathway that are involved in tumor growth andprogression. We propose the use of custom-made tissue arrays for immunohistochemistry(IHC) staining to measureexpression levels of COX-1, COX-2 and molecular markers associated with PI3K: phosphorylated AKT (pAKT),hypoxia induced factor (HIF-la) and vascular endothelial growth factor (VEGF). Parallel in vitro experiments will beperformed to further evaluate COX-1 function by treating a COX-1 expressing cell line, OVCAR3, with a selectiveCOX-1 inhibitor,SC-560. We will measure PGE2 metabolism, cell growth, apoptosis, migrationand invasion, as wellas expression levels of PI3K, pAKT, HIF-la and VEGF. We will also utilize cDNA microarrays to generate geneprofiles that are associated with COX-1. Significance: If we determine that COX-1 is indeed a prominent factor inrumor progression in ovarian cancer, this research may provide the basis for its future use as a biomarker and target fortherapy in the management of this deadly disease.
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