C SRC AND EGF RECEPTOR IN BREAST CANCER DEVELOPMENT

描述：越来越多的证据表明，表皮生长因子 受体（EGFR）和c-Src酪氨酸激酶家族在 乳腺肿瘤的发展。 两个家族都过度表达， 在许多乳腺肿瘤样品和细胞系中激活。 杂合物具有 在EGFR（HER-1）和c-Src之间以及在p185 neu（HER-2）和c-Src之间检测到了p185 neu（HER-2）。 人乳腺肿瘤细胞系和肿瘤样品中的c-Src。 此外，本发明还提供了一种方法， HER-1在EGF刺激的成纤维细胞中是致癌的，Src家族成员在EGF刺激的成纤维细胞中是致癌的。 需要EGF诱导的有丝分裂。 这些发现表明， 这两个家族在肿瘤发生过程中可能相互协作。 的 当HER-1和c-Src在10 T1/2中过表达时，证实了这一假设 成纤维细胞导致裸鼠肿瘤形成的协同增加， 小鼠 增强的肿瘤形成与 c-Src和HER-1，HER-1和HER-1上的新的c-Src依赖性磷酸化， 受体底物的体内酪氨酰磷酸化升高。 研究 这种协同作用的机制以及这种相互作用如何参与 乳腺恶性肿瘤，建议检查人乳腺肿瘤样本 以及c-Src和HER-1之间异源复合物形成的细胞系， 受体上存在新的磷酸化，以及增强的激酶 活动 c-Src和HER-1结构域的结构/功能分析 将在10 T1/2细胞中进行。 将用HER-2和c-Src进行类似的研究。 最后，c-Src来自 将检查许多肿瘤样品和细胞系以确定是否 已建立或新的激活机制正在发生，目标是 诊断试剂是否能识别激活的vs. 失活酶

DESCRIPTION: Increasing evidence suggests that the epidermal growth factor receptor (EGFR) and c-Src tyrosine kinase families have critical roles in the development of breast neoplasias. Both families are overexpressed or activated in many breast tumor samples and cell lines. Heterocomplexes have been detected between EGFR (HER-1) and c-Src and between p185neu (HER-2) and c-Src in human breast tumor cell lines and tumor samples. In addition, HER-1 is oncogenic in EGF-stimulated fibroblasts and Src family members are required for EGF-induced mitogenesis. These findings suggest that members of these two families may cooperate during tumor development. The hypothesis was confirmed when overexpression of HER-1 and c-Src in 10T1/2 fibroblasts resulted in a synergistic increase in tumor formation in nude mice. Enhanced tumor formation correlated with heterocomplexes between c-Src and HER-1, novel c-Src-dependent phosphorylations on HER-1 and elevated in vivo tyrosyl phosphorylation of receptor substrates. To study the mechanism of this synergy and how this interaction may be involved in mammary malignancies, it is proposed to examine human breast tumor samples and cell lines for heterocomplex formation between c-Src and HER-1, the presence of novel phosphorylations on the receptor, and enhanced kinase activity. A structure/function analysis of the domains of c-Src and HER-1 that are required for the synergism will be carried out in 10T1/2 cells. Similar studies will be performed with HER-2 and c-Src. Finally, c-Src from a number of tumor samples and cell lines will be examined to determine if established or novel mechanisms of activation are occurring, with the goal of determining whether diagnostic reagents would recognize activated vs. inactivated enzyme.