Breast Cancer is the number one cause of death from malignancy among women in the United States. Cancer can be induced by activation of oncogenes via different mechanisms. Overexpression of the human neu oncogene (also known as HER-2 or c-erbB-2) has been found in approximately 30% of breast tumors and correlates with poor prognosis in breast cancer patients. This clinical correlation suggests that the neu oncogene may play an important role in pathogenesis of breast cancer and can be an excellent target to develop potential anti-cancer drug. The long term goal of this proposal is to understand how the neu oncogene may contribute to development of breast cancer. In this proposal, we will focus on the role of neu oncogene in breast cancer and the molecular mechanisms that cause neu overexpression in the neu-overexpressing breast cancer cells. Therefore, the Specific Aims of this proposal are: 1. Elucidation of the role of neu gene in breast cancer. We will use anti-sense construct of neu gene or adenovirus E1A gene to block neu expression in the neu-overexpressing breast cancer cell lines and then analyze transforming activities of these breast cancer cell lines. The outcome of these experiments may provide us molecular foundation for potential therapeutic application using gene therapy for cancer patients with neu overexpressing tumors. 2. Molecular mechanisms that result in neu overexpression in breast cancer by transcriptional upregulation. We have shown in our preliminary results (Section C.2) that enhanced transcriptional rate is involved in neu overexpression in some breast cancer cell lines such as MDA-MB-453 and BT483. We will continue to study the molecular mechanisms involving transcriptional upregulation by using modern molecular biology techniques and to identify transcriptional factor(s) that upregulates neu expression in breast cancer cells. 3. Molecular mechanisms that result in neu overexpression in breast cancer by post-transcriptional upregulation. As shown in our preliminary results (Section C.3), the half-life of neu mRNA in the neu overexpressing BT474 breast cancer cell line is much longer than that in the control MCF-7 line in which neu gene is not overexpressed. We will try to identify specific RNA element(s) in neu mRNA and cellular factor(s) in the breast cancer cells that may be essential for the prolonged RNA half-life. Identification of factor(s), (from both Specific Aims 2 and 3) that directly controls neu overexpression may provide novel target(s) for development of potential anti-cancer reagents.
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