A major issue in the translation of findings from mouse models to clinical practice is the lack of appropriate tools to identify causal mechanisms of oncogenesis, tumor progression, and drug activity. The multidisciplinary project here proposed will characterize fundamental mechanisms and signaling pathways deregulated in prostate cancer through the assembly of a prostate cancer interactome, which is an accurate network of transcriptional and post-translational molecular interactions. Importantly, we will utilize reverse-engineering approaches that are unbiased and encompass the entire genome. We will use gene expression profiling of samples from different mouse models in order to have a representation of all the stages of the disease. This novel mouse to human paradigm will allow distinguishing the “drivers” of prostate cancer from the large number of “passenger” genes whose expression is coincidentally rather than causally altered in cancer progression. Key regulators will then be validated by expression analyses in mouse and human prostate cancers tissue micro-arrays to assess their relationship to disease aggressiveness and outcome. Finally, interrogation of this interactome will allow the identification of novel druggable targets for prostate cancer therapy. Candidate targets will be identified focusing first on those genes that can modulate particular signaling pathways deregulated in prostate cancer, and second on candidate targets that may induce tumor-cell specific apoptosis. Next, we will validate the expression of these candidate targets in human prostate cancer specimens, thus allowing the identification of the individuals that might benefit from specific interventions. The integrated in vivo modeling and bioinformatics study on prostate cancer proposed here will improve the capacity of the European host institution of conducting cutting edge research on this area and should constitute a significant step forward in the European leadership in the field.