Summary Missense mutations in the p53 tumor suppressor inactivate its anti-proliferative properties but can also promote metastasis through a gain-of-function activity. We show that sustained expression of mutant p53 is required to maintain the pro-metastatic phenotype of a murine model of pancreatic cancer, a highly metastatic disease that frequently displays p53 mutations. Transcriptional profiling and functional screening identified the platelet-derived growth factor receptor b (PDGFRb) as both necessary and sufficient to mediate these effects. Mutant p53 induced PDGFRb through a cell-autonomous mechanism involving inhibition of a p73/NF-Y complex that represses PDGFRb expression in p53-deficient, non-invasive cells. Blocking PDGFRb signaling by RNA interference or small molecule inhibitors prevented pancreatic cancer cell invasion in vitro and metastasis formation in vivo. Finally, high PDGFRb expression correlates with poor disease-free survival in pancreatic, colon, and ovarian cancer patients, implicating PDGFRb as a prognostic marker and possible target for attenuating metastasis in p53 mutant tumors.

A common ancestor to the three p53 family members of human genes p53, p63, and p73 is first detected in the evolution of modern-day sea anemones, in which both structurally and functionally it acts to protect the germ line from genomic instabilities in response to stresses. This p63/p73 common ancestor gene is found in almost all invertebrates and first duplicates to produce a p53 gene and a p63/p73 ancestor in cartilaginous fish. Bony fish contain all three genes, p53, p63, and p73, and the functions of these three transcription factors diversify in the higher vertebrates. Thus, this gene family has preserved its structural features and functional activities for over one billion years of evolution.

miRNAs act as oncogenes or tumor suppressors in a wide variety of human cancers, including prostate cancer (PCa). We found a severe and consistent downregulation of miRNAs, miR-154, miR-299-5p, miR-376a, miR-376c, miR-377, miR-381, miR-487b, miR-485-3p, miR-495 and miR-654-3p, mapped to the 14q32.31 region in metastatic cell lines as compared with normal prostatic epithelial cells (PrEC). In specimens of human prostate (28 normals, 99 primary tumors and 13 metastases), lower miRNA levels correlated significantly with a higher incidence of metastatic events and higher prostate specific antigen (PSA) levels, with similar trends observed for lymph node invasion and the Gleason score. We transiently transfected 10 members of the 14q32.31 cluster in normal prostatic epithelial cell lines and characterized their affect on malignant cell behaviors, including proliferation, apoptosis, migration and invasion. Finally, we identified FZD4, a gene important for epithelial-to-mesenchymal transition in (PCa), as a target of miR-377.