Human BRCA1 gene rescues the embryonic lethality of Brca1 mutant mice

Half of all familial breast cancers are due to mutation in the BRCA1 gene. However, despite its importance, attempts to model BRCA1-induced disease in the mouse have been disappointing. Heterozygous Brca1 knockout mice do not develop mammary tumors and homozygous knockout mice die during embryogenes is from ill-defined causes. Sequence analysis has shown that the coding reg ion, genomic organization, and regulatory sequences of the human and mouse genes are not well conserved. This has raised the question of whether the m ouse can serve as an effective model for functional analysis of the human B RCA1 gene. To address this question we have introduced a bacterial artifici al chromosome containing the human BRCA1 gene into the germline of Brca1 kn ockout mice. Surprisingly, we have found that the embryonic lethality of Br ca1 knockout mice is rescued by the human transgene. We also show that expr ession of human BRCA1 transgene mirrors the endogenous murine gene. Our "hu manized" transgenic mice can serve as a model system for functional analyse s of the human BRCA1 gene. genesis 29:72-77, 2001. Published 2001 Wiley-Lis s, Inc.(dagger).