Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation.
Germline mutation of the BRCA2 gene carries a high risk of developing breast cancer. To study the function of this gene, we generated a mutation in Brca2 in mice. Unlike other mutations in the Brca2 gene, which are lethal early in embryogenesis when homozygous, some of our homozygous mutant mice survive to adulthood. These animals have a wide range of defects, including small size, improper differentiation of tissues, absence of germ cells and the development of lethal thymic lymphomas. Fibroblasts cultured from BrcaZ-/-embryos have a defect in proliferation that may be mediated by over-expression of p53 and p21Waf1/CIP1. We show that Brca2 is required for efficient DNA repair, and our results suggest that loss of the p53 checkpoint may be essential for tumour progression triggered by mutations in BRCA2.
Connor
F
F
CRC Centre for Cell and Molecular Biology, Chester Beatty Laboratories, Institute of Cancer Research, London, UK.
Bertwistle
D
D
Mee
P J
PJ
Ross
G M
GM
Swift
S
S
Grigorieva
E
E
Tybulewicz
V L
VL
Ashworth
A
A
D000818:Animals; D024682:BRCA2 Protein; D001943:Breast Neoplasms / Q000196:embryology / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured; D003433:Crosses, Genetic; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D005314:Embryonic and Fetal Development / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D005804:Genes, Lethal; D018095:Germ-Line Mutation; D016399:Lymphoma, T-Cell / Q000196:embryology / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D016254:Mutagenesis, Insertional; D009363:Neoplasm Proteins / Q000235:genetics*; D013091:Spermatogenesis / Q000235:genetics; D013737:Testis / Q000473:pathology; D013953:Thymus Neoplasms / Q000196:embryology / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
D024682:BRCA2 Protein; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009363:Neoplasm Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53