Targeted deletion of the calcineurin inhibitor DSCR1 suppresses tumor growth

Cancer Cell. 2008 May;13(5):420-31. doi: 10.1016/j.ccr.2008.02.018.


The NF-AT transcription factors regulated by the phosphatase calcineurin play a role in breast cancer metastasis-promoting tumor cell invasion. Metastasis is a multistep process requiring angiogenesis and endothelial activation. NF-AT is also expressed in endothelial cells, and calcineurin-NF-AT signaling is an important downstream effector of the proangiogenic cytokine VEGF. One isoform of the endogenous calcineurin regulator, Down syndrome candidate region-1 (DSCR1.Ex4), suppresses calcineurin-NFAT signaling blocking endothelial proliferation. However, overexpression of the other DSCR1 isoform (DSCR1.Ex1) may promote angiogenesis. We report that targeted deletion of both isoforms leads to hyperactivated calcineurin and precocious endothelial apoptosis, inhibiting formation of an effective tumor vasculature and suppressing tumorigenesis. Treatment with the specific pharmacological calcineurin inhibitor cyclosporin A rescues this endothelial defect in DSCR1(-/-) mice, restoring tumor growth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcineurin / physiology
  • Calcineurin Inhibitors
  • Calcium-Binding Proteins
  • Cell Division / genetics
  • Colonic Neoplasms / blood supply*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology*
  • Endothelium, Vascular / pathology
  • Gene Deletion*
  • Intracellular Signaling Peptides and Proteins / deficiency*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Kidney Neoplasms / blood supply*
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / pathology*
  • Kinetics
  • Mice
  • Muscle Proteins / deficiency*
  • Muscle Proteins / genetics
  • Mutation
  • Necrosis
  • Neovascularization, Pathologic / genetics


  • Calcineurin Inhibitors
  • Calcium-Binding Proteins
  • DSCR1 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Muscle Proteins
  • Calcineurin