C SRC AND EGF RECEPTOR IN BREAST CANCER DEVELOPMENT

C SRC 和 EGF 受体在乳腺癌发展中的作用

• 批准号: 6164220
• 负责人: SARAH J PARSONS
• 金额: $ 25.15万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-16 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6164220
• 关键词: SCID mouse; athymic mouse; biological signal transduction; breast neoplasms; cocarcinogen; epidermal growth factor; fibroblasts; growth factor receptors; hormone related neoplasm /cancer; human tissue; neoplastic transformation; protein tyrosine kinase; protooncogene

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.

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或 在许多乳腺肿瘤样本和细胞系中被激活。 异质络合物有 在 EGFR (HER-1) 和 c-Src 之间以及 p185neu (HER-2) 和 人类乳腺肿瘤细胞系和肿瘤样本中的 c-Src。 此外， HER-1 在 EGF 刺激的成纤维细胞中具有致癌性，Src 家族成员 EGF 诱导的有丝分裂所需。 这些发现表明，成员 这两个家族可能在肿瘤发展过程中合作。 这 当 10T1/2 中 HER-1 和 c-Src 过表达时，假设得到证实 成纤维细胞导致裸鼠肿瘤形成协同增加 老鼠。 增强的肿瘤形成与异质复合物相关 c-Src 和 HER-1，HER-1 和 HER-1 上新型 c-Src 依赖性磷酸化 受体底物的体内酪氨酰磷酸化升高。 学习 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，建议检查人类乳腺肿瘤样本 以及 c-Src 和 HER-1 之间形成异源复合物的细胞系， 受体上存在新的磷酸化，并且激酶增强 活动。 c-Src 和 HER-1 结构域的结构/功能分析 协同作用所需的这些将在10T1/2细胞中进行。 类似的研究将针对 HER-2 和 c-Src 进行。 最后，c-Src 来自 将检查许多肿瘤样本和细胞系以确定是否 已建立的或新颖的激活机制正在发生，其目标是 确定诊断试剂是否能够识别激活的与未激活的 失活的酶。