Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1

Nature. 2009 Jun 25;459(7250):1126-30. doi: 10.1038/nature08062. Epub 2009 May 20.

Abstract

The incidence of many cancer types is significantly reduced in individuals with Down's syndrome, and it is thought that this broad cancer protection is conferred by the increased expression of one or more of the 231 supernumerary genes on the extra copy of chromosome 21. One such gene is Down's syndrome candidate region-1 (DSCR1, also known as RCAN1), which encodes a protein that suppresses vascular endothelial growth factor (VEGF)-mediated angiogenic signalling by the calcineurin pathway. Here we show that DSCR1 is increased in Down's syndrome tissues and in a mouse model of Down's syndrome. Furthermore, we show that the modest increase in expression afforded by a single extra transgenic copy of Dscr1 is sufficient to confer significant suppression of tumour growth in mice, and that such resistance is a consequence of a deficit in tumour angiogenesis arising from suppression of the calcineurin pathway. We also provide evidence that attenuation of calcineurin activity by DSCR1, together with another chromosome 21 gene Dyrk1a, may be sufficient to markedly diminish angiogenesis. These data provide a mechanism for the reduced cancer incidence in Down's syndrome and identify the calcineurin signalling pathway, and its regulators DSCR1 and DYRK1A, as potential therapeutic targets in cancers arising in all individuals.

Publication types

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

MeSH terms

  • Animals
  • Calcineurin / metabolism
  • Calcium-Binding Proteins
  • Catechols
  • Cells, Cultured
  • DNA-Binding Proteins
  • Disease Models, Animal
  • Down Syndrome / genetics*
  • Down Syndrome / metabolism
  • Endothelial Cells / metabolism
  • Gene Dosage / genetics
  • Humans
  • Inositol / genetics*
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Mice, Transgenic
  • Muscle Proteins / genetics*
  • Muscle Proteins / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / metabolism

Substances

  • Calcium-Binding Proteins
  • Cancell
  • Catechols
  • DNA-Binding Proteins
  • DSCR1 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Muscle Proteins
  • RCAN1 protein, human
  • Inositol
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • Calcineurin