The role of HEF1 protein in division and invasion of metastatic breast cancer

HEF1蛋白在转移性乳腺癌分裂和侵袭中的作用

基本信息

批准号：
8608492
负责人：
Elena Nikolaevna Pugacheva
金额：
$ 28.6万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8608492
关键词：
Address Affect Animal Model Antineoplastic Agents Behavior Binding Binding Sites Biological Assay Blood Breast Breast Adenocarcinoma Breast Cancer Cell Breast Cancer Model Breast Cancer Treatment Breast Melanoma Cell Culture Techniques Cell Line Cell Proliferation Cells Complex Data Deacetylation Development Diagnosis Diagnostic Neoplasm Staging Disease Disseminated Malignant Neoplasm Drug Targeting Enhancers Event Extracellular Matrix F-Actin Genes Glioblastoma Goals HDAC6 gene Histone Deacetylase Homing Human Imaging technology In Vitro Invaded Knowledge Link Malignant Epithelial Cell Malignant Neoplasms Mammary Neoplasms Measures Mediating Membrane Mesenchymal Metastatic Melanoma Metastatic to Molecular Mus Neoplasm Metastasis Pathway interactions Patients Phase II Clinical Trials Phosphorylation Phosphotransferases Play Predisposition Primary Neoplasm Process Proteins Regulation Regulatory Pathway Reporting Research Role Series Signal Transduction Site Small Interfering RNA Stream Testing Therapeutic Intervention Tissue Survival Tissues Tumor stage Ubiquitin Ubiquitination Up-Regulation Work Xenograft Model aurora-A kinase base cancer cell cancer therapy cell motility clinically relevant human EMS1 protein human disease human subject improved in vivo inhibitor/antagonist innovation insight kinase inhibitor knockout gene malignant breast neoplasm melanoma multicatalytic endopeptidase complex neoplastic cell novel overexpression prevent protein expression public health relevance research study response small molecule therapeutic target tumor tumor growth tumor progression tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): This proposal will test the hypothesis that up-regulation of the HEF1 gene in breast tumors is an important contributing factor for cancer metastasis. This is based on the ability of elevated HEF1 to drive proliferation and invasion. For invasion, cells become increasingly motile and acquire the ability to invade surrounding tissue which enables 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 HEF1 is important for glioblastoma invasiveness, and determined that upregulation of HEF1 occurred in more than 30% of metastatic melanomas. In this proposal, we will address two basic questions: 1) How does absence or overexpression of HEF1 condition AurA activation, and 2) How does HEF1 regulate invasion in breast cancer cells? In specific experiments to answer these questions, Aim 1 will use mechanistic, cell-based assays to investigate how HEF1 regulates AurA degradation. We will test the hypothesis that HEF1 protects AurA from ubiquitin-dependent proteosome degradation and determine the impact of the HEF1-AurA complex on efficacy of clinically relevant AurA inhibitors. Aim 2 will define the molecular mechanisms underlying HEF1's invasion promoting abilities. We will test the hypothesis that HEF1-activated AurA activates histone deacetylase HDAC6 and promotes deacetylation of invadopodia seeding component- cortactin. In Aim 3 we will test the hypothesis that elevated HEF1 expression contributes significantly to breast cancer metastasis using orthotopic mouse xenograft models with inducible shRNAs against HEF1 and modern multimodal non-invasive fluorescent/bioluminescent imaging technology to establish molecular mechanisms of HEF1-driven tumor growth and metastasis in human cancer. 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）：该提案将检验以下假设：乳腺肿瘤中HEF1基因的上调是癌症转移的重要因素。这是基于升高HEF1推动增殖和入侵的能力。对于侵袭，细胞变得越来越动，并获得了侵入周围组织的能力，从而使周围的组织能够转移。在过去的一年中，一系列研究提名了HEF1蛋白，作为肿瘤中促进行为的必要转换。这些研究已将HEF1确定为在转移乳腺癌腺癌中上调的基因的小“特征”的组成部分，这表明HEF1对胶质母细胞瘤的侵入性很重要，并确定在转移性黑色素瘤的30％以上。在此提案中，我们将解决两个基本问题：1）HEF1条件AURA激活的缺失或过表达如何，以及2）HEF1如何调节乳腺癌细胞中的侵袭？在回答这些问题的特定实验中，AIM 1将使用基于机械的基于细胞的测定法来研究HEF1如何调节AURA降解。我们将测试HEF1保护光环免受泛素依赖性蛋白体降解的假设，并确定HEF1-AURA复合物对临床相关AURA抑制剂功效的影响。 AIM 2将定义HEF1入侵促进能力的分子机制。我们将测试HEF1激活的Aura激活组蛋白脱乙酰基酶HDAC6并促进Invadopodia播种成分 - 皮尔塔克蛋白的脱乙酰化的假设。在AIM 3中，我们将检验以下假设：升高的HEF1表达使用原位小鼠异种移植模型具有可诱导的SHRNA和现代多模式的非偶然荧光/生物发光的想象技术来对乳腺癌转移产生重大贡献。这些实验的最终目标是改善人类患者癌症的诊断和治疗。