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。两个家庭都过度表达或 在许多乳腺肿瘤样本和细胞系中被激活。杂化络合物有 在EGFR(HER-1)和c-Src之间以及在p185neu(HER-2)和 C-Src在人乳腺肿瘤细胞系和肿瘤标本中的表达。此外, HER-1在EGF刺激的成纤维细胞中致癌，而Src家族成员是 是EGF诱导有丝分裂所必需的。这些发现表明，成员 在肿瘤的发展过程中，这两个家族中的一员可能会合作。这个 HER-1和c-Src在10T1/2细胞中过表达的假说得到证实 成纤维细胞协同增加裸体肿瘤的形成 老鼠。增强肿瘤形成与异源络合物相关 C-Src和HER-1，HER-1和HER-1上新的c-Src依赖的磷酸化 体内受体底物酪氨酸磷酸化水平升高。学习 这种协同作用的机制以及这种相互作用可能如何参与 乳腺恶性肿瘤，建议检测人类乳腺肿瘤样本 和c-Src与HER-1形成异源复合体的细胞系， 受体上存在新的磷酸化和增强的激酶 活动。C-Src和HER-1结构域的结构/功能分析 协同作用所需的物质将在10T1/2细胞中进行。 将对HER-2和c-Src进行类似的研究。最后，c-Src来自 将检查一些肿瘤样本和细胞系，以确定是否 已经建立的或新的激活机制正在发生，目标是 确定诊断试剂是否会识别激活的与 失活的酶。

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.