Cross-Species Regulatory Network Analysis Identifies a Synergistic Interaction between FOXM1 and CENPF that Drives Prostate Cancer Malignancy

•Assembly of cross-species regulatory networks supports genome-wide interrogation•Cross-species interrogation identifies conserved master regulators of malignancy•FOXM1 and CENPF interact synergistically to drive malignant prostate cancer•Co-expression of FOXM1 and CENPF is prognostic for prostate cancer outcome

SummaryTo identify regulatory drivers of prostate cancer malignancy, we have assembled genome-wide regulatory networks (interactomes) for human and mouse prostate cancer from expression profiles of human tumors and of genetically engineered mouse models, respectively. Cross-species computational analysis of these interactomes has identified FOXM1 and CENPF as synergistic master regulators of prostate cancer malignancy. Experimental validation shows that FOXM1 and CENPF function synergistically to promote tumor growth by coordinated regulation of target gene expression and activation of key signaling pathways associated with prostate cancer malignancy. Furthermore, co-expression of FOXM1 and CENPF is a robust prognostic indicator of poor survival and metastasis. Thus, genome-wide cross-species interrogation of regulatory networks represents a valuable strategy to identify causal mechanisms of human cancer.