SHP2-MEDIATED CROSS-TALK BETWEEN WNT AND EGFR/HER2 SIGNALING IN BREAST CANCER

SHP2 介导的乳腺癌中 WNT 和 EGFR/HER2 信号传导之间的串扰

• 批准号: 7720594
• 负责人: Yehenew M Agazie
• 金额: $ 24.32万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720594
• 关键词: Address; Breast; Cancerous; Cells; Computer Retrieval of Information on Scientific Projects Database; Development; Drug Delivery Systems; ERBB2 gene; Epidermal Growth Factor Receptor; Event; Funding; Grant; Institution; Knock-out; Malignant Neoplasms; Mediating; Molecular; Phosphoric Monoester Hydrolases; Phosphorylation Site; Play; Protein Overexpression; Research; Research Personnel; Resources; Role; Signal Pathway; Signal Transduction; Site-Directed Mutagenesis; Source; System; Testing; Translating; United States National Institutes of Health; cell transformation; epithelial to mesenchymal transition; in vivo; malignant breast neoplasm; mutant; therapeutic target; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long term objective of this project is to explore the potential of the Src homology phosphotyrosyl phosphatase 2 (SHP2) as a therapeutic target for the treatment of breast and other cancers characterized by overexpression of EGFR and HER2, while the current objective is to increase our understanding of SHP2 in EGFR/HER2 and ¿-catenin signaling. Therefore, the central hypothesis is that SHP2-mediated synergy between the EGFR/HER2 the ¿-catenin signaling pathways plays a major role in breast cancer development. To test this hypothesis, the following specific aims have been proposed: 1) study the molecular mechanism of SHP2 in transducing HER2 signaling and transformation and 2) investigate how SHP2 mediates ¿-catenin activation downstream of EGFR and HER2 and examine how this event translates into tumor development and epithelial-to-mesenchymal transition (EMT). To address these questions, we will employ site-directed mutagenesis of SHP2 target phosphorylation sites, expression in normal or cancerous breast cells and analysis of effect on signaling, cell transformation and in vivo tumor development. We will also use Si-RNA-mediated knockout of a-catenin to corroborate mutant expression studies; we have already developed the Si-RNA knockout system for SHP2. The relevance of this proposal is that it addresses unanswered questions in breast cancer with the potential to provide a new drug target.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 该项目的长期目标是探索SRC同源性磷酸酪蛋白磷酸酶2（SHP2）的潜力，作为治疗乳腺癌和其他癌症的治疗靶标，其特征是EGFR和HER2过度表达的癌症，而当前的目的是增加我们对EGFR/Her2和¿ -Catenin shp2中对SHP2的理解。因此，中心假设是SHP2介导的EGFR/HER2之间的协同作用 - - 帕宁蛋白信号通路在乳腺癌发育中起着重要作用。为了检验这一假设，已经提出了以下具体目标：1）研究SHP2在转导HER2信号传导和转化中的分子机制，以及2）研究SHP2如何介导EGFR和HER2的下游 - catenin激活，EGFR和HER2的下游激活并研究了这一事件如何转化为肿瘤发展到肿瘤到上层到上皮到上的杂质转换（Emeclectirition）。为了解决这些问题，我们将采用SHP2目标磷酸化位点的位置定向诱变，正常或取消的乳腺细胞中的表达以及对信号传导，细胞转化和体内肿瘤发育的影响的分析。我们还将使用SI-RNA介导的A-catenin的敲除来证实突变表达研究。我们已经开发了SHP2的SI-RNA敲除系统。该提案的相关性是它解决了乳腺癌中未解决的问题，有可能提供新的药物靶标。