The role of HEF1/NEDD9 protein in proliferation and invasion of metastatic breast cancer

HEF1/NEDD9蛋白在转移性乳腺癌增殖和侵袭中的作用

基本信息

批准号：
9981662
负责人：
Elena Nikolaevna Pugacheva
金额：
$ 35.63万
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9981662
关键词：
Adaptor Signaling Protein Affect Apoptosis Assessment tool Auras Automobile Driving Breast Cancer Patient Breast cancer metastasis Cell Line Cell Nucleus Cell Survival Cells Clinical Cytoplasm Disease Disease Progression Disease-Free Survival Drug resistance EMS1 gene ERBB2 gene Epidermal Growth Factor Receptor Genetic Polymorphism Goals Growth HDAC6 gene Impairment Incidence Knock-in Mouse Knowledge Link Malignant Neoplasms Metabolic stress Metastatic breast cancer Mitotic Molecular Molecular Target Mouse Mammary Tumor Virus Neoplasm Metastasis Nuclear Nuclear Translocation Oncogenic Pathway interactions Patients Phosphorylation Phosphotransferases Primary Neoplasm Proteins Recycling Regulation Regulatory Pathway Reporting Research Resistance Risk Assessment Role Signal Transduction Testing Therapeutic Therapeutic Intervention Transgenes Trastuzumab Tumor Cell Invasion Up-Regulation Work Xenograft procedure aurora kinase A base biomarker development breast cancer progression breast cancer survival cofilin inhibitor/antagonist late endosome malignant breast neoplasm migration mortality mouse model novel outcome forecast overexpression public health relevance trafficking treatment strategy triple-negative invasive breast carcinoma tumor tumor initiation tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): HEF1/NEDD9 is a cytoplasmic adaptor protein and a well-established marker of poor prognosis in different cancers with invasive tumor signature. We have previously reported that NEDD9 regulates stability and activation of mitotic kinase AurA/AURKA leading to phosphorylation of multiple cytoplasmic substrates, such as HDAC6, Src, CTTN, Arp/C and cofilin involved in migration and invasion. Our novel findings indicate that decrease in NEDD9 expression in TNBCs leads to translocation of AURKA to the nucleus. Presence of nuclear AURKA correlates with increase in metastatic colonization and sensitivity to AURKA inhibitors, but molecular mechanisms of this phenomenon and its role in tumor progression and metastasis is currently unknown. Interestingly, depletion of NEDD9 in HER2+ cancers decreases metastasis, thus suggesting differential role of NEDD9 in HER2+ BCs. Our novel findings indicate that NEDD9 emerges as a critical regulator of proliferation and sensitivity of HER2+ breast cancers to Herceptin via regulation of HER2 trafficking/recycling. The objective of this application is to determine the role of nuclear AURKA in metastasis in TN and HER2+ breast cancers using characterized cell lines, patient-derived xenografts and a conditional NEDD9 knock-in mouse model. Our central hypothesis is that NEDD9 is required for retention of AURKA in the cytoplasm to promote migration/invasion of tumor cells and a decrease in NEDD9 leads to nuclear translocation of AURKA, thus promoting cell survival in the metastatic niche of TNBCs. Furthermore, upregulation of NEDD9 in HER2+ BCs will lead to an increase in tumor incidence and disease progression. We will test this hypothesis by execution of the following aims: AIM 1. Determine the role of NEDD9 in AURKA cytoplasmic/nuclear translocation and the impact of nuclear AURKA on metastasis. Our hypothesis is that nuclear AURKA promotes survival and resistance to apoptosis, through the inactivation TFEB and activation of NUPR1 and Sox2 pathways. AIM 2. Elucidate the role and mechanisms by which overexpression of NEDD9 promotes HER2+ breast cancer using genetically modified mouse models and patient derived xenografts. Our hypothesis is that overexpression of NEDD9 heightens HER2-driven tumorigenesis and confers Herceptin resistance via upregulation of HER2 protein and recycling via late endosomes.

描述（由适用提供）：HEF1/NEDD9是一种细胞质适配器蛋白，是具有侵入性肿瘤特征的不同癌症中预后不良的标志。我们先前已经报道了NEDD9调节有丝分裂激酶Aura/Aurka的稳定性和激活，从而导致多种细胞质底物的磷酸化，例如HDAC6，SRC，CTTN，ARP/C和Cofilin涉及迁移和入侵。我们的新发现表明，TNBC中NEDD9表达的降低会导致Aurka转移到核。核极光的存在与转移性定植和对Aurka抑制剂的敏感性的增加相关，但是这种现象的分子机制及其在肿瘤进展和转移中的作用目前尚不清楚。有趣的是，NEDD9在HER2+癌症中的耗竭降低了转移，因此表明NEDD9在HER2+ BC中的作用差异。我们的新发现表明，NEDD9成为增殖和敏感性的关键调节剂通过监管HER2贩运/回收利用HER2+乳腺癌癌症。该应用的目的是确定核极光在TN和HER2+乳腺癌中使用特征性细胞系，患者衍生的Xenographictic和条件NEDD9敲入小鼠模型的作用。我们的中心假设是，NEDD9是在细胞质中保留Aurka所必需的，以促进肿瘤细胞的迁移/侵袭和NEDD9的降低导致Aurka的核易位，从而促进TNBC转移性nichee的细胞存活。此外，在HER2+ BC中NEDD9的上调将导致肿瘤的发病率和疾病进展增加。我们将通过执行以下目的来检验这一假设：目标1。确定NEDD9在Aurka细胞质/核易位以及核Aurka对转移的影响。我们的假设是，核Aurka通过灭活TFEB和NUPR1和SOX2途径的激活来促进凋亡的生存和抵抗力。 AIM 2。阐明NEDD9过表达使用转基因的小鼠模型和患者衍生的异种移植物促进HER2+乳腺癌的作用和机制。我们的假设是，NEDD9的过表达增强了HER2驱动的肿瘤发生，并通过上调HER2蛋白和通过晚期内体进行回收来承认赫赛汀的耐药性。