A fundamental gap in knowledge in prostate cancer (PCa) is how to distinguish indolent from aggressive disease. Further, genetic events that switch an indolent PCa to an aggressive phenotype are not well understood. Our proposed investigations will utilize two state-of-the-art genetically engineered mouse models (GEMMs) of PCa generated by the PI to address these gaps in knowledge. Expression of the Myc oncogene exclusive to mouse prostate epithelium results in indolent organ confined PCa. We have combined the Myc transgenic mouse model with additional models to establish novel GEMMs of PCa to perform a gene candidate and gene discovery approach to delineate genetic drivers of aggressive PCa progression. Specifically, aim 1 will determine if the retinoblastoma protein (Rb) is a suppressor of PCa metastasis. Specific aim 2 will utilize a sleeping beauty mutagenesis screen to identify novel candidate genetic drivers of PCa metastasis. Ultimately, these novel and state-of-the-art mouse models allow for prostate specific molecular events to be investigated. Our principle objective is to characterize our GEMMs to discover genetic switches which drive aggressive PCa. Overall, our proposed studies will significantly impact PCa research and how patients are clinically assessed to determine stratification of indolent from aggressive disease. In addition, through completing these studies, we will continue to achieve our longer term goals which are to identify and validate new therapeutic pathways/targets that may ultimately be used to treat patients with advanced PCa, and serum available biomarkers of PCa that identify aggressive PCa phenotypes.