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.
Dual specificity phosphatase 4 (DUSP4) is a potential tumor suppressor gene in breast cancer and its loss contributes to cancer stem cell-like phenotypes included circumvention of chemotherapy-induced apoptosis. Given the high frequency of DUSP4 loss (up to 50% at the single-copy level) in breast cancer, methods to exploit DUSP4 loss therapeutically could have significant clinical impact. Therefore, the goals of this proposal are to enhance our biological understanding of the anti-apoptotic role of DUSP4, while exploiting this newfound knowledge to identify novel drug targets in breast cancer.