SHP2-Mediated Synergy Between EGFR/HER2 and Beta Catenin in Breast Oncogenesis

SHP2 介导 EGFR/HER2 和 Beta 连环蛋白在乳腺肿瘤发生中的协同作用

• 批准号: 7321294
• 负责人: Yehenew M Agazie
• 金额: $ 25.05万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-16 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7321294
• 关键词: Address; Area; Breast; CCL4 gene; Cell Nucleus; Cell Proliferation; Cell Survival; Cells; Development; ERBB2 gene; Epidermal Growth Factor Receptor; Foundations; Future; Genes; Immunofluorescence Immunologic; Immunohistochemistry; Intervention Studies; Knock-out; Knockout Mice; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediating; Mediator of activation protein; Molecular; Mus; Neoplasm Metastasis; Pathway interactions; Phosphorylation Site; Phosphotransferases; Production; Protein Dephosphorylation; Protein Overexpression; Protein Tyrosine Phosphatase; Research Proposals; Signal Pathway; Signal Transduction; Site-Directed Mutagenesis; Testing; Therapeutic Intervention; Tissues; Transgenic Organisms; Work; base; beta catenin; cancer cell; cell growth; cell transformation; epithelial to mesenchymal transition; gain of function; in vivo; loss of function; malignant breast neoplasm; mutant; prognostic; receptor; research study; trait; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): The Src homology phosphotyrosine phosphatase 2 (SHP2) promotes cell proliferation and survival signals induced by receptor Tyr kinases. More specifically, SHP2 is a requisite for EGFR and HER2 signaling pathways, receptors commonly dysregulated in breast and other cancers. In addition to the Ras-ERK and PI3K-Akt signaling pathways, SHP2 transduces ?-catenin signaling downstream of the EGFR and HER2. Therefore, SHP2 acts as a mediator and integrator of these pathways, which are generally regarded as separate. Moreover, our preliminary studies show that SHP2 is overexpressed in breast tumors, suggesting that its increased expression might enhance tumor growth. However, how SHP2 positively modulates the EGFR/HER2 and the ?-catenin signaling pathways is poorly understood. Thus, this research proposal addresses the under-explored, but important area in cancer. The central hypothesis is that SHP2-mediated synergy between the EGFR/HER2 and ?-catenin signaling pathways underlies the mechanism of SHP2 in promoting epithelial-to-mesenchymal transition (EMT) and cell transformation, leading to breast tumor development. This hypothesis is based on the following findings: i) SHP2 is a positive effector of mitogenic and cell survival signals, traits dysregulated in a cancer cell, ii) SHP2 integrates ?-catenin signaling with Ras and PI3K pathways, and iii) it is overexpressed in breast cancer. The specific aims of this proposal are: 1) to explore the extent of SHP2 overexpression in breast cancer and elucidate the mechanism of action of SHP2 in HER2 signaling and transformation, 2) to study the molecular mechanism for EGFR/HER2-induced and SHP2-mediated ?-catenin activation and 3) to investigate the importance of SHP2 in HER2-induced tumorigenesis in vivo. SHP2 protein overexpression in primary breast tumors will be investigated by immunohistochemistry and immunofluorescence. The mechanism of action of SHP2 in HER2 and ?-catenin signaling will be investigated by site-directed mutagenesis, expression in appropriate cells and determining the effect of these expressions on signaling, cell growth and transformation. Finally, the importance of SHP2 in HER2-induced tumorigenesis will be studied in HER2 transgenic and SHP2 knockout (specifically in the mammary gland) mice.

描述（由申请人提供）：SRC同源性磷酸酪氨酸磷酸酶2（SHP2）促进了受体Tyr激酶诱导的细胞增殖和存活信号。更具体地说，SHP2是EGFR和HER2信号通路的必要条件，即在乳腺癌和其他癌症中通常失调的受体。除了RAS-ERK和PI3K-AKT信号通路外，SHP2还会转导？-CATENIN信号在EGFR和HER2的下游。因此，SHP2充当这些途径的中介和集成剂，通常被视为单独。此外，我们的初步研究表明，SHP2在乳腺肿瘤中过表达，这表明其表达增加可能会增强肿瘤的生长。但是，SHP2如何积极地调节EGFR/HER2和-CATENIN信号通路的理解很差。因此，该研究提案涉及癌症中未经探索但重要的领域。中心假设是SHP2介导的EGFR/HER2和？ - 卡丁蛋白信号通路之间的协同作用是SHP2在促进上皮到间质转变（EMT）和细胞转化方面的机理，导致乳腺肿瘤的发展。该假设基于以下发现：i）SHP2是有丝分裂和细胞存活信号的积极效应，特征在癌细胞中失调的特征，ii）SHP2与RAS和PI3K途径的-Catenin信号整合在一起，以及III）在乳腺癌中过表达。该提案的具体目的是：1）探索乳腺癌中SHP2过表达的程度，并阐明SHP2在HER2信号传导和转化中的作用机制，2），研究EGFR/HER2诱导的分子机制，并诱导的SHP2诱导的和SHP2介导的介导的shp2 ins 2-inf tulorig in 2-in 2-诱导了shp2 in 2 in 2-诱导。原发性乳腺肿瘤中的SHP2蛋白过表达将通过免疫组织化学和免疫荧光研究。 SHP2在HER2和？ - 蛋白信号传导中的作用机理将通过位置定向的诱变，在适当的细胞中的表达进行研究，并确定这些表达式对信号传导，细胞生长和转化的影响。最后，将在HER2转基因和SHP2敲除（特别是在乳腺中）小鼠中研究SHP2在HER2诱导的肿瘤发生中的重要性。