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: 6690649
• 负责人: SARAH J PARSONS
• 金额: $ 0.39万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6690649
• 关键词: athymic mouse; breast neoplasms; epidermal growth factor; genetically modified animals; growth factor receptors; neoplastic growth; oncoproteins; phosphoproteins; phosphorylation; protein structure function; protooncogene; tissue /cell culture

DESCRIPTION (provided by applicant): Members of the epidermal growth factor receptor (EGFR) and c-Src tyrosine kinase families are frequently co-overexpressed in human neoplasias. This co-overexpression suggests that members of the two families may functionally interact to affect tumor formation and/or progression. Results from recent studies in both a model fibroblast system and in human breast cancer cell lines and tumor tissues have indicated that c-Src and EGFR synergistically interact to promote tumor formation. Evidence also supports a functional interaction between c-Src and two other members of the EGFR family, HER2 and HER3. The potentiation of EGFR-mediated tumor formation by c-Src correlates with EGF-induced physical association of the EGFR with c-Src, c-Src-dependent phosphorylation of the receptor at two novel sites (Y845 and Yl101), and increased tyrosine phosphorylation of selected receptor substrates. Substitution of phenylalanine for Y845 ablates EGF- and serum-induced DNA synthesis, suggesting that phosphorylation of Y845 may be a critical regulator of EGF-mediated growth and may represent a novel target to be exploited for tumor therapy. However, whether this site is required for malignant transformation mediated by the EGFR is not known, nor is the mechanism of phospho-Y845 (pY845) action understood. Similarly, the mechanism of the interplay between HER2/3 and c-Src is unknown. To further investigate the dependency of EGF-induced breast cancer cell growth and tumorigenesis on pY845 and the nature of the HER2/3/c-Src interaction, the ability of an inducibly expressed mutant Y845F EGFR or microinjected peptides containing pY845 to inhibit breast cancer cell growth in culture or in nude mice will be directly tested, as will biological synergism between c-Src and EGFR and its dependency on Y845 phosphorylation in a transgenic mouse model. The downstream effectors of phosphorylated Y845 will also be identified from a panel of known EGFR substrates and from differential phage display libraries, using phosphorylated vs. unphosphorylated peptides containing Y845 as probes. Finally the influence of c-Src on HER2/3-promoted cell survival, growth, and migration will be explored in two cell culture/xenograft models that will allow one to investigate the interaction in a normal (not transformed) cell context. The long-term goal of these studies is to understand the biological consequences of c-Src/EGFR family member interactions and the biochemical mechanisms that underlie them, thereby identifying potential new targets for therapeutic intervention of breast and other cancers.

描述（由申请人提供）：表皮生长因子的成员 受体（EGFR）和C-SRC酪氨酸激酶家族经常是 共同表达人类肿瘤。这种共同表达表明 两个家族的成员在功能上可能相互作用以影响肿瘤的形成 和/或进展。两种模型成纤维细胞的最新研究结果 系统和人类乳腺癌细胞系和肿瘤组织已表明 该C-SRC和EGFR协同相互作用以促进肿瘤形成。 证据还支持C-SRC与另外两个的功能相互作用 EGFR家族，HER2和HER3的成员。 EGFR介导的增强 C-SRC形成肿瘤与EGF诱导的物理关联有关 具有C-SRC的EGFR，在两个受体的C-SRC依赖性磷酸化 新颖的地点（Y845和YL101），并增加了酪氨酸磷酸化的 选定的受体底物。替代苯丙氨酸Y845灌溉 EGF和血清诱导的DNA合成，表明Y845的磷酸化 可能是EGF介导的生长的关键调节剂，可能代表一种新颖 靶标被利用用于肿瘤治疗。但是，这个网站是否是 由EGFR介导的恶性转化所必需的，尚不清楚，也不是 理解了磷酸Y845（PY845）作用的机制。同样， HER2/3和C-SRC之间相互作用的机制尚不清楚。进一步 研究EGF诱导的乳腺癌细胞生长的依赖性和 PY845的肿瘤发生及其HER2/3/C-SRC相互作用的性质， 诱导表达的突变体Y845F EGFR或显微注射肽的能力 包含PY845以抑制培养或裸体中乳腺癌细胞的生长 小鼠将直接测试，C-SRC和 EGFR及其对转基因小鼠模型中Y845磷酸化的依赖性。 还将从A中鉴定出磷酸化Y845的下游效应子 已知的EGFR基板和差异噬菌体显示库的面板， 使用磷酸化与未磷酸化的肽作为探针。 最后，C-SRC对HER2/3促进细胞存活，生长和 将在两个细胞培养/异种移植模型中探索迁移 一个用于研究正常（未转化）细胞环境中的相互作用。 这些研究的长期目标是了解生物学 C-SRC/EGFR家庭成员互动和生化的后果 基于它们的机制，从而确定了潜在的新目标 乳房和其他癌症的治疗干预。