Ovarian cancer is responsible for the highest mortality rate among patients with gynecological malignancy. Studies on molecular mechanisms that cause human ovarian cancer may lead to development of novel means for predicting and possibly treating these aggressive malignancies. Overexpression of the HBR-2/neu (also known as c-erbB-2) oncogene which encodes a growth factor receptor-like molecule is frequently found in human ovarian cancer and correlates with poor survival for patients with ovarian cancer. The long-term goal of this proposal is to understand the tumor biology of human ovarian cancer. The current proposal will focus on the role of HBR-2/neu and its ligand, Heregulin in the development of human ovarian cancer.
The specific aims are: Biological Effects of HER-2/neu Overexpression in Ovarian Cancer Cells. By transfection of HBR-2/neu expression vectors into appropriate ovarian cancer cell lines, the changes in their biological properties will be studied. These experiments will provide crucial data to determine the role of HER-2/neu overexpression in malignancies of ovarian cancer. Modulation of Tyrosine Kinase Activity by the Ligand-Binding Domain (LBD) of the HER-2/neu Receptor in Human Ovarian Cancer Cells: Molecular Mechanisms and Biological Effects. The effects of LBD on autophosphorylation and trans-phosphorylation of HER-2/neu tyrosine kinase will be determined and compared to the effects of LBD on the biological properties. If LBD can repress tyrosine kinase activity of HER-2/neu receptor and therefore suppress malignant phenotypes of HER-2/neu- overexpressing ovarian cancer cells, the LBD of HER-2/neu will serve as a novel reagent for understanding tumor biology of ovarian cancer and may have potential value in ovarian cancer therapy. Biological Effects of Heregulin in Ovarian Cancer Cells. Heregulin expression vectors will be used to modulate Heregulin expression in ovarian cancer cell lines and the biological effects of Heregulin on these cells will be measured. The proposed experiments will provide critical information on the potential role of Heregulin in human ovarian cancer. Model Systems for Ovarian Tumor Growth through Paracrine Interactions Between HER-2/neu and Heregulin. Potential paracrine loops between Heregulin and HER-2/neu will be tested by model systems. The proposed experiments will use modern molecular and cellular biology techniques to ask how HER-2/neu receptor and its ligand, Heregulin, may contribute to the malignancy of human ovarian cancer cells. The outcome of this proposal will advance our understanding on basic tumor biology of human ovarian cancer.
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