Women carrying germ-line mutations in BRCA1 are strongly predisposed to developing breast cancers with characteristic features also observed in sporadic basal-like breast cancers. They appear as high-grade tumors with high proliferation rates and pushing borders. On the molecular level, they are negative for hormone receptors and ERBB2, display frequent TP53 mutations, and express basal epithelial markers. To study the role of BRCA1 and P53 loss of function in breast cancer development, we generated conditional mouse models with tissue-specific mutation of Brca1 and/or p53 in basal epithelial cells. Somatic loss of both BRCA1 and p53 resulted in the rapid and efficient formation of highly proliferative, poorly differentiated, estrogen receptor-negative mammary carcinomas with pushing borders and increased expression of basal epithelial markers, reminiscent of human basal-like breast cancer. BRCA1-and p53-deficient mouse mammary tumors exhibit dramatic genomic instability, and their molecular signatures resemble those of human BRCA1-mutated breast cancers. Thus, these tumors display important hallmarks of hereditary breast cancers in BRCA1-mutation carriers.mouse models ͉ conditional knockout G erm-line mutations in the human breast cancer susceptibility gene BRCA1 are responsible for 40% to 50% of hereditary breast cancers and confer increased risk for development of ovarian, colon, and prostate cancers (1, 2). BRCA1 has been implicated in various cellular processes, including maintenance of genome integrity, DNA replication and repair, chromatin remodeling, and transcriptional regulation (3, 4). Although the exact mechanism of mammary tumor suppression by BRCA1 remains largely unknown, cells with dysfunctional BRCA1 show defects in survival and proliferation, increased radiosensitivity, chromosomal abnormalities, G 2 /M checkpoint loss, and impaired homologous recombination repair (5).BRCA1-mutated breast cancers that arise in women with germline mutations in BRCA1 are high-grade, hormone receptornegative breast carcinomas with frequent mutation of TP53 (4, 6). They also possess a basal-like phenotype as defined by the expression of markers that are typical for basal/myoepithelial cells, such as the basal cytokeratins (CKs) CK5/6 and CK14 (7). Indeed, strong molecular similarities are observed between hereditary BRCA1-mutated breast cancers and sporadic basal-like breast carcinomas (8,9). This phenotypic overlap has led to the hypothesis that sporadic basal-like cancers may have defects in BRCA1-related pathways, such as the amplification of EMSY and the methylation of BRCA1 and FANCF (10).Despite the fact that several mouse strains with conventional or conditional mutations in Brca1 have been generated (11), no good mouse model for BRCA1-mutated basal-like breast cancer has been developed so far. Most conventional Brca1 knockouts are embryonic-lethal when bred to homozygosity, yet heterozygous ⌬11 allele, which encodes BRCA1-⌬11, a naturally occurring splice variant of Brca1 (19). Mouse mammary tumor models ba...