Deleted in Colorectal Carcinoma Suppresses Metastasis in p53-deficient Mammary Tumours

Nature. 2012 Feb 22;482(7386):538-41. doi: 10.1038/nature10790.

Abstract

Since its discovery in the early 1990s the deleted in colorectal cancer (DCC) gene, located on chromosome 18q21, has been proposed as a tumour suppressor gene as its loss is implicated in the majority of advanced colorectal and many other cancers. DCC belongs to the family of netrin 1 receptors, which function as dependence receptors as they control survival or apoptosis depending on ligand binding. However, the role of DCC as a tumour suppressor remains controversial because of the rarity of DCC-specific mutations and the presence of other tumour suppressor genes in the same chromosomal region. Here we show that in a mouse model of mammary carcinoma based on somatic inactivation of p53, additional loss of DCC promotes metastasis formation without affecting the primary tumour phenotype. Furthermore, we demonstrate that in cell cultures derived from p53-deficient mouse mammary tumours DCC expression controls netrin-1-dependent cell survival, providing a mechanistic basis for the enhanced metastatic capacity of tumour cells lacking DCC. Consistent with this idea, in vivo tumour-cell survival is enhanced by DCC loss. Together, our data support the function of DCC as a context-dependent tumour suppressor that limits survival of disseminated tumour cells.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cell Line, Tumor
  • Cell Survival / genetics
  • DCC Receptor
  • Disease Models, Animal
  • Female
  • Genes, p53 / genetics*
  • Mammary Neoplasms, Experimental / genetics*
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Metastasis / genetics*
  • Neoplasm Metastasis / pathology*
  • Nerve Growth Factors / deficiency
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism
  • Netrin-1
  • Receptors, Cell Surface / deficiency
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • DCC Receptor
  • Dcc protein, mouse
  • Nerve Growth Factors
  • Ntn1 protein, mouse
  • Receptors, Cell Surface
  • Tumor Suppressor Proteins
  • Netrin-1