VARIANT PRODUCTS OF HER-/NEU IN BREAST CANCER

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DESCRIPTION: (Applicant's Description) The erbB family of transmembrane receptor tyrosine kinases transmit signals that are essential to growth and differentiation and their abundance in breast cancers has implicated these receptors in malignant disease. One member of this family, HER-2/neu, correlates with disease recurrence, shorter survival, and possibly with response to adjuvant endocrine and chemotherapy. However, conflicting results, particularly in node-negative patients, suggest limited utility of HER-2/neu as a prognostic marker. We have recently discovered variant products of HER-2/neu that would not be distinguished in conventional assays of clinical specimens. In addition to p185HER-2/neu, two truncated variants, one with the ligand binding domain and a second with an activated kinase domain, are independently expressed at high levels in a subgroup of patients. We hypothesize that the truncated variant proteins have differing prognostic significance because of their diverse signalling capacities. The goal of this project is to investigate breast tumor tissue for presence and activation state of variant forms of HER-2/neu and to correlate these forms with tumor stage and patient outcome to indicate their significance in prognosis and malignant progression. To investigate expression and activation of the variant forms to HER-2/neu we will use specific antibodies for immunoprecipitation and Western blot analysis of breast cancer tissue. Results of these experiments will determine (1) levels of p185 and the variant ligand binding domain (LBD-p100) and kinase domain (KD-p80), (2) activation state of p185 and variant kinase domain (KD-p80) by tyrosine phosphorylation levels, kinase activity and by association with phospholipase C gamma, and (3) association of p185HER-2/neu variant forms with disease stage and patient outcome.