Ovarian cancer (OC) is a major cause of death for women in the United States. The American Cancer Society predicts 23,000 new cases in the year 2000 and 14,000 women die each year because of this disease. Although all cell types of the human ovary may undergo neoplastic transformation, the vast majority (80-90%) of malignant tumors is derived from a single layer of epithelial cells covering the ovarian surface. Understanding the cause and mechanisms responsible for ovarian epithelial cancer at the molecular level and development of novel treatment and prevention strategies are greatly needed to combat this deadly disease. Epidemiological studies have implicated high levels of ovarian steroids and gonadotropins during and after menopause, as probable risk factors of OC. In preliminary study and published studies, we found 1) substantial levels of follicle stimulating hormone (FSH) receptors and estrogen receptor a and b on human ovarian surface epithelial (HOSE) cells. 2) FSH and estradiol profoundly stimulated HOSE cell growth. 3) cDNA microarray analysis revealed differential gene expression profiles of FSH treated and non-treated cells that are of relevance to the process of ovarian carcinogenesis. 4) HOSE cells exposed to low concentration (10-9 M) of diethylstilbesterol (DES) ? FSH for four weeks acquired anchored-independent growth ability, a phenotype associate with neoplastic transformation. Based on these findings we, hypothesize 1) that transformation of HOSE cells may occur under the influence of high levels of FSH and or estrogen and 2) that the early transformants express cancer-specific molecular markers. Capitalizing on our access to several immortalized normal HOSE cell lines, we shall 1) determine the molecular pathways associated with FSH and estrogen-induced HOSE cell growth, 2) determine the gene expression profile of normal and hormonally transformed HOSE cells using two powerful molecular methodologies. Gene expression profiling of normal and transformed HOSE cells will be performed using NEN microarray of 2400 genes and unknown genes will be identified by suppression substractive hybridization (SSH). Results from these studies will 1) help to identify early OC markers, which is a key for secondary cancer prevention, and 2) enhance our understanding of ovarian carcinogenesis, which may lead to unique intervention strategies.
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