Unravelling prostate cancer genetics
Researchers comprehensively characterised the PC interactome (PCi) during the course of the project PC INTERACTOME. PCi refers to the entire genome network of transcriptional and post-translational molecular interactions that occur during PC progression. Researchers successfully generated the mouse PCi using data from 14 different genetically engineered mouse (GEM) models. They compiled almost 400 gene expression profiling datasets with genetic, phenotypic and pharmacologic diversity. Using the 'Algorithm for the reconstruction of accurate cellular networks' (ARACNe) algorithm, one of the project partners developed the datasets. Combining chromatin immunoprecipitation and DNA sequencing the scientists validated results from the PCi predictions. Comparison of all the selected transcription factors (TFs) such as BCL6, MYC, AR and ER as well as their targets revealed a significant overlap. A mouse model of metastatic cancer was used to identify phenotypic variations that are linked to aggressive cancers. Extensive characterisation of mouse model was carried out and published in a peer-reviewed journal (Proceedings of the National Academy of Sciences of the United States of America, PNAS). PC INTERACTOME compared metastatic with non-metastatic tumours and revealed master regulators involved in cancer progression that could be useful biomarkers for predicting disease outcome. In particular, the expression levels of forkhead box M1 (FOXM1) and centromere protein F (CENPF) were tested in silico along with studies on prostate cancer specimens. Gene silencing experiments revealed that synergistic activation of FOXM1 and CENPF was found in more aggressive forms of PC. Patients with higher levels of FOXM1 or CENPF proteins had higher chances of survival than those with elevated levels of both these proteins. Studies on PC cell lines helped identify altered signalling pathways that are associated with FOXM1 and/or CENPF. An important finding was the identification of signalling pathways relevant to tumourigenesis following co-silencing of FOXM1 and CENPF. This included the MAP kinase pathway and PI3 kinase signalling pathway. Scientists also successfully identified genes involved in the enrichment of such signalling. The assembly of the human and mouse interactomes, as well as all the biochemical and functional validation studies leading to the identification of FOXM1 and CENPF as master regulators of prostate cancer aggressiveness were published in a peer-reviewed journal (Cancer Cell). Project outcomes have set the stage for more effective PC management. Novel therapeutic targets may result using the knowledge generated during the project.
