HER-2/NEU ALTERATIONS IN BREAST AND OVARIAN CANCER

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Human breast and ovarian cancer together account for 162,000 new cases of cancer per year or essentially one third of all cancers occurring in women. In addition, they account for 55,000 deaths per year, or essentially one quarter of cancer related deaths in women. The HER-2/neu proto-oncogene is a putative growth factor receptor which is related to, but distinct from the epidermal growth factor receptor. Studies done in our laboratory have shown that this gene is amplified and/or overexpressed in ~30% of human breast and ovarian cancers. Moreover, this alteration is associated with a poor clinical outcome for patients in whose tumors it occurs. The objective of this proposal is to investigate the possible role this alteration plays in the pathogenesis of these diseases. Transfection studies will be done to convert human breast and ovarian cells from cells with a single copy and low levels of expression of the HER-2/neu gene to cells with an amplified/overexpressed gene mimicking the alteration found in human breast and ovarian cancer. The biologic effects of this alteration will be investigated, including effects on DNA synthesis, cell growth, cell invasiveness, and tumorigenicity in the nude mouse. In addition, antibodies to extracellular domains of this gene product will be used in vitro and in vivo studies of cells containing this alteration to determine if the antibodies change the biologic effects mediated by this alteration. These studies may lead to development of novel therapeutic approaches to these diseases based on this oncogene alteration.