Transcriptome profiling of dorsal prostate from four mouse genotypes : wild-type, LXRalpha/beta KO, PTENpc-/- and LXRalpha/beta KO PTENpc-/-

Advanced prostate cancer (PCa) is a clinical challenge as this state of the disease lacks of curative therapeutic. We exploited human datasets as well as mouse models to decipher mechanisms able to constrain cancer evolution in response to genetic alteration that occurs in PCa. Careful analysis of transcriptomic signature of various PCa datasets reveals activation of the LXR target gene signature. This LXR signature is tightly correlated to PTEN-loss in human. Causal LXR deregulation has been confirmed using prostate mouse carcinomas from Pten-null mutant. Protective role of LXR has been demonstrated by their deletions in a Pten-null context in mouse prostate, thus results in an increase of PCa invasiveness and metastatic dissemination. PTEN deletion governs LXR transcriptional activity through deregulation of cholesterol de novo synthesis that leads to the accumulation of LXR ligands. According to these observations, pharmacological inhibition of cholesterol biosynthesis using statins abolishes LXR target gene expression in response to PTEN-loss. LXR deletion triggers an increased in the epithelial mesenchymal transition process and matrix metalloproteinase accumulations that could explain metastatic spreading. This work highlights LXRs as metabolic sensors that act as gatekeeper able to constrain carcinoma progression.

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