Project Summary Prostate cancer is the second leading cause of cancer related death in men in the United States. Many of the newly diagnosed patients are indolent and would not die from prostate cancer even if they are left untreated. But lack of reliable markers to identify such indolent tumors has led to overtreatment of patients. To minimize overtreatment, patients with a lower Gleason Score are put on active surveillance and are not treated unless there is sign of disease progression. Although such active surveillance can minimize over-treatment, it may miss the opportunity for early intervention of aggressive tumors. Therefore, understanding molecular mechanisms underlying the aggressive nature of prostate cancer and identifying prognostic markers to distinguish indolent from aggressive prostate cancers are of great clinical significance. Human prostate cancers mostly originate in the peripheral zone (PZ). In addition, transition zone (TZ) tumors are often associated with favorable pathological features and better recurrence-free survival. These observations lead to the hypothesis that the differences in tissue microenvironment between the two zones influence the frequency and aggressiveness of the resulting tumors. We compared gene expression profiles between TZ and PZ stroma by an RNA-seq analysis and identify the transcription factor FOXF2 as one of the top genes expressed at a higher level in TZ stromal cells. We demonstrated that elevated Foxf2 expression in prostate stromal cells suppressed growth of prostate cancer xenografts in vivo. In Aim1, we will use genetically engineered mouse models to confirm that stromal Foxf2- mediated signaling suppresses tumor progression. In Aim 2, we will investigate the molecular mechanisms through which stromal Foxf2 suppresses tumor progression. In Aim 3, we will investigate how stromal FOXF2 expression is regulated.