SMAD4-dependent Barrier Constrains Prostate Cancer Growth and Metastatic Progression

Nature. 2011 Feb 10;470(7333):269-73. doi: 10.1038/nature09677. Epub 2011 Feb 2.

Abstract

Effective clinical management of prostate cancer (PCA) has been challenged by significant intratumoural heterogeneity on the genomic and pathological levels and limited understanding of the genetic elements governing disease progression. Here, we exploited the experimental merits of the mouse to test the hypothesis that pathways constraining progression might be activated in indolent Pten-null mouse prostate tumours and that inactivation of such progression barriers in mice would engender a metastasis-prone condition. Comparative transcriptomic and canonical pathway analyses, followed by biochemical confirmation, of normal prostate epithelium versus poorly progressive Pten-null prostate cancers revealed robust activation of the TGFβ/BMP-SMAD4 signalling axis. The functional relevance of SMAD4 was further supported by emergence of invasive, metastatic and lethal prostate cancers with 100% penetrance upon genetic deletion of Smad4 in the Pten-null mouse prostate. Pathological and molecular analysis as well as transcriptomic knowledge-based pathway profiling of emerging tumours identified cell proliferation and invasion as two cardinal tumour biological features in the metastatic Smad4/Pten-null PCA model. Follow-on pathological and functional assessment confirmed cyclin D1 and SPP1 as key mediators of these biological processes, which together with PTEN and SMAD4, form a four-gene signature that is prognostic of prostate-specific antigen (PSA) biochemical recurrence and lethal metastasis in human PCA. This model-informed progression analysis, together with genetic, functional and translational studies, establishes SMAD4 as a key regulator of PCA progression in mice and humans.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins / metabolism
  • Cell Proliferation
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Disease Progression*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor / physiology
  • Humans
  • Lung Neoplasms / secondary
  • Lymphatic Metastasis
  • Male
  • Mice
  • Mice, Transgenic
  • Models, Biological
  • Neoplasm Invasiveness / genetics
  • Neoplasm Invasiveness / pathology
  • Neoplasm Metastasis / genetics
  • Neoplasm Metastasis / pathology*
  • Osteopontin / genetics
  • Osteopontin / metabolism
  • PTEN Phosphohydrolase / deficiency
  • PTEN Phosphohydrolase / genetics
  • Penetrance
  • Prognosis
  • Prostate / metabolism
  • Prostate-Specific Antigen / metabolism
  • Prostatic Neoplasms / diagnosis
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology*
  • Smad4 Protein / deficiency
  • Smad4 Protein / genetics
  • Smad4 Protein / metabolism*
  • Transforming Growth Factor beta

Substances

  • Bone Morphogenetic Proteins
  • Ccnd1 protein, mouse
  • SPP1 protein, human
  • Smad4 Protein
  • Smad4 protein, mouse
  • Spp1 protein, mouse
  • Transforming Growth Factor beta
  • Osteopontin
  • Cyclin D1
  • PTEN Phosphohydrolase
  • Pten protein, mouse
  • Prostate-Specific Antigen

Associated data

  • GEO/GSE25140