VARIANT PRODUCTS OF HER-/NEU IN BREAST CANCER

描述：(申请人的描述)跨膜的erbB家族 受体酪氨酸激酶传递对生长和生长至关重要的信号 乳腺癌中的分化和它们的丰富性与这些 恶性疾病中的受体。这个家庭的一名成员，Her-2/neu， 与疾病复发、生存期缩短有关，可能还与 对辅助内分泌和化疗的反应。然而，矛盾的是 结果，特别是在结节阴性的患者中，表明应用有限。 HER-2/neu作为预后标志物。我们最近发现了变种 HER-2/neu的产物，在常规检测中无法区分 临床标本。除了p185HER-2/neu外，还有两个截断 变异体，一个具有配体结合结构域，第二个具有激活的 在一个亚群中独立地高水平表达 病人。我们假设截短的变异蛋白具有不同的 由于它们具有不同的信号传递能力，因此具有预后意义。这个 该项目的目标是研究乳腺肿瘤组织的存在和 HER-2/neu变异形式的激活状态及其相互关系 与肿瘤分期和患者预后的关系，以表明它们在 预后和恶性进展。 研究HER-2/neu变异体的表达和激活 我们将使用特定的抗体进行免疫沉淀和Western印迹 乳腺癌组织的分析。这些实验的结果将 测定(1)p185和变异型配体结合域的水平 (LBD-P100)和激酶结构域(KD-P80)，(2)p185和 酪氨酸磷酸化水平变化的蛋白激酶结构域(KD-p80) 活性和与磷脂酶C-γ的关联，以及(3)关联 P185HER-2/neu变异与疾病分期和患者预后的关系。

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.