Functional role of p130Cas/BCAR1 in breast cancer

p130Cas/BCAR1 在乳腺癌中的功能作用

• 批准号: 7001327
• 负责人: Kathrin H Kirsch
• 金额: $ 29.1万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7001327
• 关键词: apoptosis; breast neoplasms; clinical research; disease /disorder etiology; epidermal growth factor; gene expression; genetically modified animals; growth factor receptors; human tissue; laboratory mouse; mammary epithelium; mammary gland; molecular oncology; natural gene amplification; neoplasm /cancer genetics; neoplastic cell; neoplastic transformation; protein structure function; proteins; reproductive development; tamoxifen; yeast two hybrid system

Adapter proteins are integrally involved in the intracellular regulation of diverse signaling events including the control of cellular proliferation, differentiation, adhesion, and motility. One of the key regulators in EGF receptor and c-Src signaling is the adapter protein p130Cas. Treatment of cells with EGF or EGF-related ligands leads to the phosphorylation and activation of p130Cas, which is augmented by the expression of c-Src. Deregulation of these pathways due to aberrant activation of EGF receptor family members or c-Src may contribute to the development of breast cancer, as elevated protein levels of p130Cas/BCAR1 in primary breast tumors are associated with poor prognosis and poor overall survival. We hypothesize that p130Cas is instrumental in the development and progression of tumors of the mammary gland induced by aberrant expression of EGF receptor-family tyrosine kinases and c-Src. The objectives of this application are to understand the biological role of p130Cas in breast cancer in vivo and during development of the mammary gland. Here experiments are proposed to use mouse models and cells in culture to characterize the role of p130Cas and its activation in tumorigenesis of breast epithelial cells; a combined approach correlating in vivo studies on function with in vitro analysis of mechanisms of action will be employed. Specifically aims are we proposed to: 1) Determine the functional role of p130Cas activity in breast cancer cells in vitro. 2) Analyze human breast tissue for gene amplifications leading to increased p130Cas. 3) Identify new signaling intermediates that interact physically with the p130Cas substrate domain in a tyrosine-dependent manner. 4) Determine the role of p130Cas in mammary gland development and breast cancer in vivo. These studies will provide important information on the role and mechanism of p130Cas expression in the pathogenesis of breast cancer and mammary gland development. The detailed knowledge of p130Cas in transformation and the identification of downstream effectors may uncover important new therapeutic targets for novel treatment modalities.

衔接蛋白在细胞内调节各种信号传导事件中的调节，包括控制细胞增殖，分化，粘附和运动。 EGF受体和C-SRC信号传导中的关键调节剂之一是衔接蛋白P130CAS。用EGF或与EGF相关的配体对细胞的处理导致P130CAS的磷酸化和激活，这通过C-SRC的表达增强。由于EGF受体家族成员或C-SRC的异常激活而导致的这些途径可能会导致乳腺癌的发展，因为原发性乳腺肿瘤中P130CAS/BCAR1的蛋白质水平升高与预后不良和整体生存率差有关。我们假设P130CA在EGF受体 - 家庭酪氨酸激酶和C-SRC的异常表达引起的乳腺肿瘤的发育和进展中发挥了作用。该应用的目标是了解P130CA在体内和乳腺发育过程中的生物学作用。这里提出了在培养物中使用小鼠模型和细胞来表征p130cas的作用及其在乳腺上皮细胞肿瘤发生中的作用的实验。将采用将功能研究与动作机理的体外分析相关的合并方法。我们提出的特定目的是：1）确定P130CAS活性在体外乳腺癌细胞中的功能作用。 2）分析人类乳腺组织的基因扩增，导致P130CAS增加。 3）确定以酪氨酸依赖性方式与P130CAS底物结构域进行物理相互作用的新信号传导中间体。 4）确定P130CA在体内乳腺发育和乳腺癌中的作用。这些研究将提供有关P130CAS表达在乳腺癌和乳腺发育发育中的作用和机制的重要信息。 P130CAS在转化方面的详细知识以及对下游效应子的识别可能会发现新型治疗方式的重要新治疗靶标。