Mitotic checkpoint inactivation fosters transformation in cells lacking the breast cancer susceptibility gene, Brca2.
The murine Brca2 gene encodes a nuclear protein implicated in DNA repair. Brca2 behaves as a tumor suppressor, but paradoxically, its truncation causes proliferative arrest and spontaneous chromosomal damage. Here, we report that inactivation of cell cycle checkpoints responsive to mitotic spindle disruption, by mutant forms of p53 or Bub1, relieves growth arrest and initiates neoplastic transformation in primary cells homozygous for truncated Brca2. Tumors from Brca2-deficient animals exhibit dysfunction of the spindle assembly checkpoint, accompanied by mutations in p53, Bub1, and Mad3L. The chromosomal aberrations precipitated by Brca2 truncation can be suppressed by mutant forms of Bub1 and p53. Thus, inactivating mutations in mitotic checkpoint genes likely cooperate with BRCA2 deficiency in the pathogenesis of inherited breast cancer, with important implications for treatment.
Lee
H
H
Medical Research Council, Laboratory of Molecular Biology, Cambridge, United Kingdom.
Trainer
A H
AH
Friedman
L S
LS
Thistlethwaite
F C
FC
Evans
M J
MJ
Ponder
B A
BA
Venkitaraman
A R
AR
D000818:Animals; D024682:BRCA2 Protein; D001943:Breast Neoplasms / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D004249:DNA Damage; D052138:Genes, Neoplasm; D016147:Genes, Tumor Suppressor; D006801:Humans; D007399:Interphase; D008223:Lymphoma / Q000235:genetics; D051379:Mice; D008938:Mitosis / Q000235:genetics*; D009154:Mutation; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases; D012190:Retroviridae / Q000235:genetics; D008941:Spindle Apparatus / Q000235:genetics; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000494:pharmacology
D024682:BRCA2 Protein; D009363:Neoplasm Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; C584277:BUB1 protein, human; C584281:Bub1 protein, mouse; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases