The effects of dietary energy balance on PCa progression using the HiMyc mouse model have been studied to gain greater insight into the mechanisms and to identify potential targets for prevention strategies. Thirty percent calorie restriction (CR) significantly reduced PCa progression whereas, diet-induced obesity (DIO) led to more rapid progression of PCa in this mouse model, findings similar to that seen in men with PCa. DIO also significantly increased (and 30% CR decreased) numbers of T-lymphocytes and macrophages in the ventral prostate (VP) compared with overweight control. Further experiments have shown that the mRNA expression of inflammatory and angiogenesis mediators in RNA samples from VP was significantly increased in the DIO group compared with both the overweight control and CR diet groups. Further analyses showed that enhanced growth factor (Akt/mTORC1 and STAT3) and inflammatory (NF-kappaB and cytokines) signaling in the tumors may play a role in dietary energy balance effects on PCa progression in HiMyc mice. Using a procedure to separate the stromal-vascular fraction (SVF) [containing adipose stromal cells (ASCs), inflammatory cells and endothelial cells] we have analyzed the production of a number of inflammatory cytokines and chemokines as well as growth factors. Further studies have suggested that CXCL12/CXCR4 signaling may play an important role in driving PCa progression in HiMyc mice during obesity through selective effects on PCa stem cells. Based on these data and other data to be presented, we have evaluated several agents (e.g. metformin, rapamycin, 6-shogaol, ursolic acid and others for their ability to prevent PCa development and/or progression using the HiMyc model. Overall, these studies are leading to a greater understanding of the impact of dietary energy balance on PCa development and progression as well as identifying novel strategies for PCa prevention and for offsetting the effects of obesity on PCa progression.