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

• 批准号: 9061648
• 负责人: Justin M Balko
• 金额: $ 25.06万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9061648
• 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 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; 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; 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; cancer subtypes; career; career development; chemotherapeutic agent; chemotherapy; clinically relevant; docetaxel; improved; improved outcome; in vivo Model; inhibitor/antagonist; lectures; malignant breast neoplasm; mouse model; neoplastic cell; new therapeutic target; novel; promoter; restoration; screening; skills; targeted agent; targeted treatment; therapeutic target; therapy resistant; triple-negative invasive breast carcinoma; tumor

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.

项目总结/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的专业知识，同时解决知识的根本差距 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/R 00 我职业生涯的过渡阶段将是我作为一名独立调查员成功发展的一个组成部分， 一流的研究机构本文概述的培训计划将利用广泛的资源， 在范德比尔特大学以及关键的高级人员与科学卓越的跟踪记录， 作为导师和合作者。 作为我独立之路的一部分，我在范德比尔特组建了一个指导团队， 发展建议和科学指导。由范德比尔特提供的教学研讨会、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，并将进一步帮助我准备一个独立的教师职位。技术研讨会由 杰克逊人类癌症实验模型实验室以及生物信息学的两个研讨会将 在本建议的早期阶段采取行动，以加强对以下方面的科学和技术知识： 基因工程小鼠模型，并扩大我在生物信息学的专业知识和技能，这两个主要 本文概述的工作特点。 该提案的科学部分侧重于实验和机械测试的潜在作用， DUSP 4是乳腺癌耐药的介导因子。DUSP 4是双特异性磷酸酶， 对ERK 1/2和JNK 1/2的活性，MAPK途径的关键信号组分。我们先前已经 显示DUSP 4丢失，部分是由于表观遗传沉默，在基底样和腔型B乳腺癌中很常见， 并有助于抵抗化疗诱导的细胞凋亡。我们自己公布的数据和初步的 本申请中的数据支持DUSP 4作为乳腺癌耐药性介质的作用， 这表明遗传或表观遗传DUSP 4缺失可能是治疗上可利用的分子改变， 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 DUSP 4丢失抑制化疗诱导的细胞凋亡的机制以及这如何 规避，和2）在同基因细胞系中使用高通量siRNA筛选> 7，500个基因靶标 其缺乏或表达DUSP 4，以便鉴定具有DUSP 4缺失的乳腺癌中的合成致死靶。 完成这项建议的科学目标将发展我在实验模型方面的研究技能， 同时也为临床试验提供了理论基础，以克服乳腺癌的治疗耐药性。 DUSP 4缺陷型乳腺癌最后，该提案旨在确定新的治疗靶点， 影响乳腺癌治疗。