Cas Protein Regulation of EMT in Cancer

Cas 蛋白对癌症 EMT 的调节

• 批准号: 8102942
• 负责人: ERICA A. GOLEMIS
• 金额: $ 29.32万
• 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/8102942
• 关键词: Address; Adherens Junction; Automobile Driving; Behavior; Biological Assay; Breast; Breast Adenocarcinoma; Carcinoma in Situ; Cell Line; Cell membrane; Cells; Characteristics; Cytoskeleton; Diagnosis; E-Cadherin; ERBB2 gene; Elements; Epithelial; Epithelial Cells; Gene Amplification; Genes; Glioblastoma; Goals; Human; Immigration; Integrins; Invaded; Loss of E-cadherin Expression; Lung; Malignant Neoplasms; Mammary Neoplasms; Maps; Mesenchymal; Metastatic Melanoma; Modeling; Molecular; Monomeric GTP-Binding Proteins; Morbidity - disease rate; Mouse Mammary Tumor Virus; Mus; Neoplasm Metastasis; Non-Malignant; Oncogenes; Oncogenic; PTK2 gene; Pathway interactions; Patients; Pattern; Phosphotransferases; Polyomavirus; Process; 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 genomics; 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; overexpression; 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（由申请人提供）：该提案将测试以下假设：肿瘤中 HEF1 基因的上调是癌症转移的重要影响因素，基于升高的 HEF1 在 EMT 中驱动上皮间质转化 (EMT) 的能力。细胞失去上皮细胞特征，变得越来越能动，并获得侵入周围组织的能力，从而实现转移。这些研究已确定 HEF1 是转移性乳腺腺癌中上调基因的一个组成部分，表明 HEF1 对于胶质母细胞瘤侵袭性很重要，并确定 HEF1 的上调发生在更多的细胞中。超过 30% 的转移性黑色素瘤，并且对于转移过程至关重要 自从我们小组于 1996 年首次描述 HEF1 基因以来，我们一直在不断努力。这项工作证明了 HEF1 作为支架蛋白或“枢纽”的核心作用，可增强和协调促进癌症进展的多个信号级联的活性。 ：1) HEF1 过度表达的缺失或升高如何影响经典的 EMT/转移反应，包括 E-钙粘蛋白的表达？ 2) HEF1 的表达升高是乳腺癌转移的重要决定因素吗？为了回答这些问题，目标 1 将使用基于细胞的机制分析来研究 HEF1 如何调节 EMT，我们将测试 HEF1 通过直接控制 E-钙粘蛋白在粘附连接处形成稳定结构的能力来促进 EMT 的假设。并确定 HEF1 是否是 TGF-¿ 的重要中间体目标 2 将使用基因定义的 HEF1-/- 小鼠来测试提高 HEF1 表达的能力对乳腺癌转移有显着影响的假设。我们将把 HEF1-/- 小鼠与两种转基因小鼠品系杂交。 MMTV-PyVT 和 MMTV-neu）可形成原发性乳腺肿瘤和肺转移，并确定 HEF1 的缺失是否限制转移，以及 TGF-¿最后，目标 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改善人类患者癌症的诊断和治疗。