Dusp4 in breast cancer: tumor suppressor biology and therapeutic strategies

描述（由申请人提供）：这条独立职业发展之路提案的目标是请求支持培训，以发展乳腺癌实验模型的专业知识，同时解决可能对乳腺癌患者治疗产生重大影响的知识方面的根本差距。在我职业生涯的过渡阶段，K99/R 00的支持将是我成功发展为一家顶级研究机构的独立研究员的不可或缺的一部分。本文概述的培训计划将利用范德比尔特大学的广泛资源以及具有卓越科学记录的关键高级人员作为导师和合作者。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，提供职业发展建议和科学指导。由范德比尔特和生物研究教育和培训（BRET）办公室提供的教学研讨会，讲座和讲习班将为这一指导提供结构化的支持，并将帮助我进一步准备一个独立的教师职位。杰克逊实验室提供的关于人类癌症实验模型的技术研讨会以及生物信息学的两个研讨会将在本提案的早期阶段进行，以增强基因工程小鼠模型的科学和技术知识，并扩展我在生物信息学方面的专业知识和技能，这两个方面都是本文概述的工作的主要特点。该提案的科学部分侧重于实验和机械测试DUSP 4作为乳腺癌耐药性介质的潜在作用。DUSP 4是一种双特异性磷酸酶，对MAPK通路的关键信号组分ERK 1/2和JNK 1/2具有活性。我们以前已经表明，DUSP 4的损失，部分通过表观遗传沉默，是常见的基底样和管腔B乳腺癌，并有助于抵抗化疗诱导的细胞凋亡。我们自己发表的数据和本申请中的初步数据支持DUSP 4作为乳腺癌耐药性介导剂的作用，并表明遗传或表观遗传DUSP 4缺失可能是肿瘤细胞内治疗上可利用的分子改变。因此在 根据这些数据，我将探索两个首要的科学目标：1）确定DUSP 4缺失抑制化疗诱导的细胞凋亡的机制以及如何规避这种机制，以及2）使用高通量siRNA筛选缺乏或表达DUSP 4的同基因细胞系中的> 7，500个基因靶标，以鉴定DUSP 4缺失的乳腺癌中的合成致死靶标。完成本提案的科学目标将发展我在乳腺癌实验模型方面的研究技能，同时也为临床试验克服DUSP 4缺陷乳腺癌的治疗耐药性奠定基础。最后，该提案旨在确定可能影响乳腺癌治疗的新治疗靶点。

DESCRIPTION (provided by applicant): 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.