Dusp4 in breast cancer: tumor suppressor biology and therapeutic strategies

Dusp4 在乳腺癌中的作用：肿瘤抑制生物学和治疗策略

基本信息

批准号：
9044055
负责人：
Justin M Balko
金额：
$ 24.9万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-04-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9044055
关键词：
Ablation Address Affect Apoptosis Apoptotic Automobile Driving Bioinformatics Biological Biology Breast Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment Breast Cancer therapy Cell Line Cells Chemotherapy-Oncologic Procedure Cisplatin Clinical Clinical Trials Cytotoxic Chemotherapy Data Dependence Development Diagnosis Doxorubicin Drug Targeting Drug resistance ERBB2 gene Educational workshop Epigenetic Process Estrogen Receptors Experimental Models Faculty Feedback Frequencies Future Gene Expression Profile Gene Targeting Genes Genetic Genetically Engineered Mouse Genome Genomics Goals Human Human Resources Institution Knowledge Learning Libraries MAP Kinase Gene MAPK3 gene MAPK8 gene MEKs Malignant Neoplasms Mammary Neoplasms Mass Spectrum Analysis Mediating Mediator of activation protein Mentors Methods Methylation Mitogen-Activated Protein Kinase Inhibitor Modeling Molecular Molecular Target Outcome Pathway interactions Patients Phase Phenotype Phosphoric Monoester Hydrolases Population Positioning Attribute Publishing Records Regulation Research Research Personnel Resistance Resources Role Signal Pathway Signal Transduction Small Interfering RNA Specificity Structure Testing Therapeutic Therapeutic Agents Training Training Support Training and Education Tumor Suppressor Genes Tumor Suppressor Proteins Universities Woman Work Xenograft Model Xenograft procedure anticancer research base biological research cancer stem cell career career development chemotherapeutic agent chemotherapy clinically relevant docetaxel improved in vivo Model inhibitor/antagonist lectures malignant breast neoplasm mouse model neoplastic cell new therapeutic target novel promoter restoration screening skills therapeutic target therapy resistant triple-negative invasive breast carcinoma tumor

项目摘要

PROJECT SUMMARY/ABSTRACT The goals of this Pathway to Independence Career Development Proposal are to request support for training to develop expertise in experimental models of breast cancer while addressing a fundamental gap in knowledge that could have a significant impact on the treatment of breast cancer patients. K99/R00 support during this transitional phase of my career will be integral to my successful development as an independent investigator at a top-tier research institution. The training plan outlined herein will take advantage of the extensive resources available at Vanderbilt University as well as key senior personnel with track records of scientific excellence to serve as mentors and collaborators. As part of my pathway to independence I have assembled a mentoring team at Vanderbilt to provide career development advice and scientific direction. Didactic seminars, lectures, and workshops provided by Vanderbilt and the Biological Research Education and Training (BRET) office will provide structured support for this guidance and will help further prepare me for an independent faculty position. A technical workshop offered by Jackson Labs on the Experimental Models of Human Cancer as well as two workshops in Bioinformatics will be taken during the earlier phase of this proposal in order to enhance scientific and technical knowledge on genetically engineered mouse models and to expand my expertise and skills in Bioinformatics, both major features of the work outlined herein. The scientific portion of this proposal focuses on experimentally and mechanistically testing the potential role of DUSP4 as a mediator of drug resistance in breast cancer. DUSP4 is a dual-specificity phosphatase with activity against ERK1/2 and JNK1/2, key signaling components of the MAPK pathways. We have previously shown that DUSP4 loss, in part by epigenetic silencing, is common in basal-like and luminal B breast cancer, and contributes to resistance to chemotherapy-induced apoptosis. Our own published data and the preliminary data in this application support a role for DUSP4 as a mediator of drug resistance in breast cancer, and suggest that genetic or epigenetic DUSP4 loss may be a therapeutically exploitable molecular alteration within the tumor cell. Therefore, in line with these data I will explore two overarching scientific aims; 1) to determine the mechanism by which DUSP4 loss inhibits chemotherapy-induced apoptosis and how this can be circumvented, and 2) to use high-throughput siRNA screening for >7,500 gene targets in isogenic cell lines which lack or express DUSP4 in order to identify synthetic lethal targets in breast cancers with DUSP4 loss. The completion of the scientific aims of this proposal will develop my research skills in experimental models of breast cancer while also developing the rationale for clinical trials to overcome therapeutic resistance in DUSP4-deficient breast cancer. Finally, this proposal seeks identify novel therapeutic targets which could impact breast cancer treatment.

项目概要/摘要本独立之路职业发展提案的目标是请求培训支持发展乳腺癌实验模型方面的专业知识，同时解决基本的知识差距这可能对乳腺癌患者的治疗产生重大影响。在此期间支持K99/R00 我职业生涯的过渡阶段对于我作为一名独立调查员的成功发展至关重要一流的研究机构。本文概述的培训计划将利用广泛的资源范德比尔特大学以及具有卓越科学记录的关键高级人员充当导师和合作者。作为独立之路的一部分，我在范德比尔特组建了一个指导团队，为我提供职业指导发展建议和科学方向。范德比尔特大学提供的教学研讨会、讲座和讲习班生物研究教育和培训（BRET）办公室将为此提供结构化支持指导并将帮助我进一步为独立教职职位做好准备。由以下机构提供的技术研讨会杰克逊实验室关于人类癌症的实验模型以及两个生物信息学研讨会将在本提案的早期阶段采取，以加强有关方面的科学和技术知识基因工程小鼠模型并扩展我在生物信息学方面的专业知识和技能，这两个专业本文概述的工作特点。该提案的科学部分侧重于通过实验和机械测试的潜在作用 DUSP4 作为乳腺癌耐药性的介质。 DUSP4 是一种双特异性磷酸酶针对 ERK1/2 和 JNK1/2（MAPK 通路的关键信号传导成分）的活性。我们之前有过表明 DUSP4 缺失（部分是由于表观遗传沉默所致）在基底样乳腺癌和管腔 B 型乳腺癌中很常见，并有助于抵抗化疗诱导的细胞凋亡。我们自己发布的数据和初步本申请中的数据支持 DUSP4 作为乳腺癌耐药性介质的作用，并且表明遗传性或表观遗传性 DUSP4 缺失可能是一种可用于治疗的分子改变肿瘤细胞。因此，根据这些数据，我将探索两个总体科学目标； 1）确定 DUSP4 缺失抑制化疗诱导的细胞凋亡的机制及其如何实现规避，2) 使用高通量 siRNA 筛选同基因细胞系中 >7,500 个基因靶标缺乏或表达 DUSP4，以便识别 DUSP4 缺失的乳腺癌中的合成致死靶点。完成该提案的科学目标将提高我在实验模型方面的研究技能乳腺癌，同时还为克服乳腺癌治疗耐药性的临床试验奠定了基础 DUSP4 缺陷型乳腺癌。最后，该提案寻求确定新的治疗靶点，这些靶点可以影响乳腺癌的治疗。