Cas Protein Regulation of EMT in Cancer

Cas 蛋白对癌症 EMT 的调节

• 批准号: 7321244
• 负责人: ERICA A. GOLEMIS
• 金额: $ 29.21万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-03 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7321244
• 关键词: Address; Adherens Junction; Automobile Driving; Behavior; Biological Assay; Breast; Breast Adenocarcinoma; Carcinoma in Situ; Cell Line; Cell membrane; Cells; Characteristics; Condition; Cytoskeleton; Diagnosis; E-Cadherin; ERBB2 gene; Elements; Elevation; End Point; Epithelial; Epithelial Cells; Gene Amplification; Genes; Glioblastoma; Goals; Human; Immigration; Integrins; Invaded; Invasive; Loss of E-cadherin Expression; Lung; Malignant Neoplasms; Mammary Neoplasms; Maps; Mesenchymal; Metastatic Melanoma; Modeling; Molecular; Monomeric GTP-Binding Proteins; Morbidity - disease rate; Mus; Neoplasm Metastasis; Non-Malignant; Oncogenes; Oncogenic; PTK2 gene; Pathway interactions; Patients; Pattern; Phosphotransferases; Polyomavirus; Process; Protein Overexpression; Proteins; Regulation; Relative (related person); Role; Scaffolding Protein; Series; Signal Pathway; Signal Transduction; Solid Neoplasm; Source; Structure; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Tumor-Derived; Up-Regulation; Work; base; cancer therapy; cell motility; comparative genomic hybridization; epithelial to mesenchymal transition; human BCAR1 protein; improved; in vivo; malignant breast neoplasm; melanoma; metastatic process; migration; mortality; neoplastic cell; programs; protein E; protein expression; receptor; research study; response; tumor; tumor progression

DESCRIPTION (provided by applicant): This proposal will test the hypothesis that upregulation of the HEF1 gene in tumors is an important contributing factor for cancer metastasis, based on the ability of elevated HEF1 to drive epithelial-mesenchymal transition (EMT). In EMT, cells lose epithelial cell characteristics, become increasingly motile, and acquire the ability to invade surrounding tissue, enabling metastasis. A series of studies within the past year have nominated the HEF1 protein as an essential switch for pro-metastatic behavior in tumors. These studies have identified HEF1 as a component of a small "signature" of genes upregulated in metastasizing breast adenocarcinomas, shown that HEF1 is important for glioblastoma invasiveness, and determined that upregulation of HEF1 occurred in more than 30% of metastatic melanomas and was critical for the metastatic process. Since our group first described the HEF1 gene in 1996, we have worked continually to dissect the signaling role of this protein. This work has demonstrated a central role for HEF1 as a scaffolding protein or "hub" that enhances and coordinates the activity of multiple signaling cascades that promote cancer progression. In this proposal, we will address two basic questions: 1) How does absence or elevation of HEF1 overexpression condition classic EMT/metastatic responses, including expression of E-cadherin? and 2) Is elevated expression of HEF1 an important determinant of breast cancer metastasis? In specific experiments to answer these questions, Aim 1 will use mechanistic, cell-based assays to investigate how HEF1 regulates EMT. We will test the hypothesis that HEF1 promotes EMT by directly controlling the ability of E-cadherin to form stable structures at adherens junctions, and determine whether HEF1 is an essential intermediate in TGF-¿ or ErbB2-induced EMT. Aim 2 will use genetically defined HEF1-/- mice to test the hypothesis that the ability to elevate HEF1 expression contributes significantly to breast cancer metastasis. We will cross HEF1-/- mice to two strains of transgenic mice (MMTV-PyVT and MMTV-neu) that develop primary breast tumors and lung metastases, and determine whether absence of HEF1 limits metastasis, and conditions TGF-¿ and ErbB2-related signaling in tumor cells. Finally, Aim 3 will ask if elevated HEF1 predicts a metastatic profile in human breast tumors. The ultimate goal of these experiments is to improve the diagnosis and treatment of cancer in human patients.

描述(申请人提供)：这项提案将基于HEF1基因上调驱动上皮-间充质转化(EMT)的能力，来检验这一假设，即肿瘤中HEF1基因的上调是癌症转移的重要因素。在EMT中，细胞失去了上皮细胞的特征，变得越来越能动，并获得了侵入周围组织的能力，从而使转移成为可能。在过去的一年里，一系列研究已经提名HEF1蛋白作为促进肿瘤转移行为的重要开关。这些研究已经确定HEF1是转移性乳腺癌中上调的一小部分基因的一个组成部分，表明HEF1对胶质母细胞瘤的侵袭性很重要，并确定HEF1的上调发生在超过30%的转移性黑色素瘤中，并且在转移过程中起关键作用。自从我们的小组在1996年首次描述HEF1基因以来，我们一直在不断地研究这种蛋白的信号作用。这项工作证明了HEF1作为支架蛋白或“枢纽”的核心作用，它增强和协调促进癌症进展的多个信号级联的活动。在这个提案中，我们将解决两个基本问题：1)HEF1过表达的缺失或升高如何影响典型的EMT/转移反应，包括E-钙粘附素的表达？2)HEF1的高表达是否是乳腺癌转移的重要决定因素？在回答这些问题的具体实验中，目标1将使用机械的、基于细胞的分析来研究HEF1是如何调节EMT的。我们将验证HEF1通过直接控制E-钙粘蛋白在黏附连接形成稳定结构的能力来促进EMT的假设，并确定HEF1是否是转化生长因子β或ErbB2诱导的EMT的必要中间产物。目的2将使用基因定义的HEF1-/-小鼠来验证这样的假设，即上调HEF1表达的能力显著有助于乳腺癌的转移。我们将把HEF1-/-小鼠与两种转基因小鼠(MMTV-PyVT和MMTV-neu)进行杂交，以发展原发乳腺肿瘤和肺转移，并确定缺乏HEF1是否限制转移，以及调节肿瘤细胞中与转化生长因子β和ErbB2相关的信号。最后，Aim 3将询问HEF1升高是否可以预测人类乳腺肿瘤的转移情况。这些实验的最终目标是提高人类患者癌症的诊断和治疗水平。