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 d...

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Bibliographic Details
Published in:Molecular cell 1999-07, Vol.4 (1), p.1-10
Main Authors: Lee, Hyunsook, Trainer, Alison H, Friedman, Lori S, Thistlethwaite, Fiona C, Evans, Martin J, Ponder, Bruce A.J, Venkitaraman, Ashok R
Format: Article
Language:English
Subjects:
Animals
BRCA2 Protein
Breast Neoplasms - genetics
Cell Transformation, Neoplastic - genetics
Cells, Cultured
Chromosome Aberrations
DNA Damage
Genes, Neoplasm
Genes, Tumor Suppressor
Humans
Interphase
Lymphoma - genetics
Mice
Mitosis - genetics
Mutation
Neoplasm Proteins - deficiency
Neoplasm Proteins - genetics
Protein Kinases - genetics
Protein Kinases - pharmacology
Protein-Serine-Threonine Kinases
Retroviridae - genetics
Spindle Apparatus - genetics
Transcription Factors - deficiency
Transcription Factors - genetics
Transfection
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - pharmacology
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Summary: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.
ISSN:1097-2765
1097-4164
1097-4164
DOI:10.1016/S1097-2765(00)80182-3