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. B rca2 behaves as a tumor suppressor, but paradoxically, its truncation cause s proliferative arrest and spontaneous chromosomal damage. Here, we report that inactivation of cell cycle checkpoints responsive to mitotic spindle d isruption, by mutant forms of p53 or Bub1, relieves growth arrest and initi ates neoplastic transformation in primary cells homozygous for truncated Br ca2. 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 c heckpoint genes likely cooperate with BRCA2 deficiency in the pathogenesis of inherited breast cancer, with important implications for treatment.