TNF GENE REGULATION IN BREAST AND OVARY CANCER

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There is growing evidence that TNF-alpha may play an important role in the pathogenesis of some malignancies. It appears that production of TNF-alpha by malignant cells occurs in some human cancers including ovarian cancer and neuroblastoma. In human ovarian cancer, TNF-alpha has been implicated as a paracrine and autocrine growth factor. TNF-alpha may also increase chemosensitivity to certain drugs including taxol and cisplatin, the most active drugs in the treatment of ovary cancer. Autocrine production of TNF-alpha produces resistance to the antiproliferative effects of TNF-alpha in epithelial cancer cells. However, the regulation of TNF-alpha expression in malignant epithelial cells is very poorly understood. This renewal represent extension of previous studies of TNF-alpha gene regulation in human epithelial cancer cells. Breast and ovary cancer models of autocrine TNF-alpha production first identified in our laboratory will be utilized. We will examine the molecular biology of TNF-alpha gene regulation in human epithelial cancer cells through studies of both the 5' flanking region and the 3' region of the human TNF-alpha gene. Early response genes, including c-fos and the jun family appear to be key participants in epithelial tumor cell regulation of TNF-alpha. These laboratory studies will be accompanied by studies of clinical samples from patients with ovarian carcinoma to examine the importance of TNF-alpha in ovarian cancer pathogenesis. The specific aims will be: 1. To investigate the importance of the TNF- alpha 5' flanking region in the regulation of TNF-alpha gene regulation in human breast and ovary cancer cells through reporter gene constructs and gel shift assays; 2. To investigate the importance of the AP-1 motif in the control of TNF production in human epithelial cancer cells with sense and antisense c-jun constructs; 3. To evaluate the role of the TNF-alpha 3' flanking region in the regulation of TNF-alpha protein production in human epithelial cancer cells with 3' flanking region reporter gene constructs; 4. To examine human epithelial ovarian cancers from our ovarian cancer tissue bank to better define the relationships between TNF-alpha expression and ovarian cancer pathophysiology. Taken together, these studies will provide insight into the pathobiology of ovarian cancer and possibly provide new strategies for ovarian cancer therapy.