ABSTRACT: Key histological and growth progression characteristics of human prostate cancer are phenocopied in mouse models that have been subjected to androgen level depletion and engineered for hemizygosity of candidate prostate cancer tumor suppressor genes Nkx3.1 and Pten. To characterize their relative transcriptomes and identify a genomic basis for their relevance to human prostate cancers, we compared mouse prostate tumors expression profiles to those from a panel of human prostate cancer isolates and to normal and benign prostates. Human prostate cancers and mouse prostate tumor models both exhibit the activation of genes associated with growth, cell cycle control, and inhibition of differentiation (CDKN2A, CDKN2B, CDKN2C, CEBPB, CEBPG, CSF1, CTSS, DMBT1, EGFR, PLCG2, PXN, SPP1, TNFSF9), and conversely, diminished expression of genes associated with normal prostate differentiation and function. All tumors also exhibit dysregulated expression of genes associated with inflammation, the disruption of prostate-associated ER stress pathways, as well as with oxidative stress, energy metabolism, cell adhesion, and stress response. Immunoinflammatory and altered cell adhesion process-associated genes exhibited prominent expression in early stage tumors. In contrast, metastatic human prostate cancer samples eliminated the expression of most immunoinflammatory-associated transcripts. Cross-species comparisons of molecular programs that are shared or distinguishing of Nkx3.1; Pten mutant mouse models and human adenocarcinomas clearly delineate core tumorigenesis programs associated with cell cycle activation and loss of differentiation. Compared to locally spreading mouse and human tumors, metastatic prostate cancer exhibits greatly reduced expression of immunoinflammatory and adhesion genes, implying that immuno-inflammatory activation may enable first stages of tumorogenesis, but suppress metastasis. These results provide a novel framework to identify stage-specific biomarkers and candidate targets for combinatorial therapeutics. The complex role of inflammation suggests a need for additional caution in countering metastasis. Keywords: tumor stage
