The human breast and ovarian cancer susceptibility gene, BRCA1, has recently been cloned. BRCA1 encodes a protein of unknown function, although it may be a tumor suppressor gene. The mutant alleles are predicted to be null alleles or loss-of-function mutations. To study the role of BRCA1 in tumorigenesis, we have created a mouse with a null allele at the BRCA1 locus. This targeted disruption results in an embryonic lethal phenotype. Therefore, we are attempting to create mice with conditional knock-outs of BRCA1, so that we can knock-out the gene only in the breast. In addition, we have created transgenic lines expressing BRCA1 from the CMV promoter. The developmental and tumor phenotype of mice with gain- and loss-of-function mutations of BRCA1 will be studied.