Targeted deletion of the calcineurin inhibitor DSCR1 suppresses tumor growth.
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.
Ryeom
Sandra
S
Vascular Biology Program, Department of Surgery, Children's Hospital, Boston, MA 02115, USA. sandra.ryeom@childrens.harvard.edu
Baek
Kwan-Hyuck
KH
Rioth
Matthew J
MJ
Lynch
Ryan C
RC
Zaslavsky
Alexander
A
Birsner
Amy
A
Yoon
Sam S
SS
McKeon
Frank
F
D000818:Animals; D019703:Calcineurin / Q000502:physiology; D065095:Calcineurin Inhibitors; D002135:Calcium-Binding Proteins; D002455:Cell Division / Q000235:genetics; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000473:pathology*; D004730:Endothelium, Vascular / Q000473:pathology; D017353:Gene Deletion; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D007680:Kidney Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000473:pathology*; D007700:Kinetics; D051379:Mice; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics; D009154:Mutation; D009336:Necrosis; D009389:Neovascularization, Pathologic / Q000235:genetics
D065095:Calcineurin Inhibitors; D002135:Calcium-Binding Proteins; C511512:DSCR1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D019703:Calcineurin