TARGETED MUTATIONS OF BREAST-CANCER SUSCEPTIBILITY GENE HOMOLOGS IN MICE - LETHAL PHENOTYPES OF BRCA1, BRCA2, BRCA1 BRCA2, BRCA1/P53, AND BRCA2/P53 NULLIZYGOUS EMBRYOS/

Mutations of the human BRCA1 and BRCA2 genes encoding turner suppresso rs have been Implicated in inherited predisposition to breast and othe r cancers. Disruption of the homologous mouse genes Brca1 and Brca2 by targeting showed that they both have indispensable roles during embry ogenesis,;because nullizygous embryos become developmentally retarded and disorganized, and die early in development. In Brca1 mutants, the onset of abnormalities is earlier by one day and their phenotypic feat ures and time of death are highly variable, whereas the phenotype of B rca2 null embryos is more uniform, and they all survive for at least 8 .5 embryonic days. Observations with Brca1/Brca2 double nullizygotes r aise the possibility that the two developmental pathways could be link ed. Interestingly, the impact of the Brca1 or Brca2 null mutation is L ess severe in a p53 null background.