The human HER-2/neu gene encodes a growth factor receptor which belongs to the type I receptor tyrosine kinase family. It is now generally accepted that the alteration of this gene plays some critical role in the pathogenesis of the 25-30 percent of human breast cancers in which is it amplified and overexpressed causing the cancers to behave particularly aggressively in patients. As a result of this observation, this genetic alteration has been successfully targeted using the monoclonal antibody Herceptin which is directed against the extra cellular domain of the receptor. During the prior period of support of this project, many of the phenotypic abnormalities associated with this alteration have been identified and shown to be consistent with an aggressive clinical phenotype, i.e. increase growth in vitro, increased tumorigenicity in vivo and increase metastatic potential in orthotopic implantation models. The molecular pathways and mechanisms by which these phenotypic changes are mediated, however, remain only partially elucidated. It is the purpose of this proposal to continue and expand research efforts directed at dissecting the molecular events downstream of this alteration in order to gain a better understanding of this event and perhaps identify molecular targets that would make therapeutic approaches to this alteration even more effective. To that end, four specific aims will be undertaken, including. The further characterization of signaling pathways associated with HER-2/neu overexpression, as well as the similarities and differences in these pathways induced by an agonist (heregulin, NDF) and an antagonist (Herceptin); the expansion on data generated from Specific Aim I to evaluate the changes in the PI3 kinases signaling pathway related to the AKT 2 sgne which appears to be important in the HER-2/neu phenotype; the identification of differentially expressed genes in HER-2 overexpressing versus matched non-overexpressing cells, as well as cells treated with an agonist (heregulin) and antagonist (Herceptin); and finally the characterization of any unique genes identified at the protein and cellular levels, i.e. identification of the encoded protein, characterization of its half life, expression pattern in normal and malignant tissues, and functional studies if indicated.
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