Dusp4 in breast cancer: tumor suppressor biology and therapeutic strategies

项目摘要/摘要 《独立职业发展之路》提案的目标是请求对培训提供支持 发展乳腺癌实验模型方面的专业知识，同时解决知识的根本差距 这可能会对乳腺癌患者的治疗产生重大影响。在此期间提供K99/R00支持 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不可或缺的一部分 一家顶级研究机构。本文概述的培训计划将利用广泛的资源 在范德比尔特大学提供，以及拥有卓越科学记录的关键高级人员 充当导师和合作者。 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，为我的职业生涯 发展建议和科学方向。由Vanderbilt提供的教学研讨会、讲座和工作坊 生物研究教育和培训(BRET)办公室将为此提供有组织的支持 并将帮助我为独立教职做好进一步的准备。由提供的技术研讨会 杰克逊人类癌症实验模型实验室和两个生物信息学研讨会将 在本提案的较早阶段采取行动，以增进关于 基因工程小鼠模型和扩展我在生物信息学方面的专业知识和技能，这两个主要 本文概述的工作特点。 这项建议的科学部分集中在实验和机械测试的潜在作用 DUSP4在乳腺癌耐药中的作用DUSP4是一种双特异性磷酸酶，具有 针对MAPK通路的关键信号成分ERK1/2和JNK1/2的活性。我们之前已经 研究表明，DUSP4缺失，部分是由于表观遗传沉默，在基底细胞样癌和腔性B型乳腺癌中很常见， 并有助于抵抗化疗诱导的细胞凋亡。我们自己公布的数据和初步的 本申请中的数据支持DUSP4作为乳腺癌耐药的介体的作用，以及 提示遗传性或表观遗传性DUSP4缺失可能是一种治疗上可利用的分子改变 肿瘤细胞。因此，根据这些数据，我将探索两个最重要的科学目标：1)确定 DUSP4缺失抑制化疗诱导的细胞凋亡的机制及其机制 绕过，以及2)使用高通量siRNA筛选等基因细胞系中的7,500个基因靶点 它们缺失或表达DUSP4，以便在DUSP4缺失的乳腺癌中识别合成的致死靶点。 这项建议的科学目标的完成将培养我在实验模型中的研究技能 乳腺癌的同时也为临床试验克服治疗耐药性提供了理论基础 DUSP4缺陷型乳腺癌。最后，这项提议寻求确定新的治疗靶点，这些靶点可以 影响乳腺癌的治疗。

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.