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Previous <jats:italic>Brca1<\/jats:italic>\u2010heterozygous animal models do not recapitulate the breast cancer phenotype, and thus all currently used knockout models adopt conditional, mammary\u2010specific homozygous <jats:italic>Brca1<\/jats:italic> loss or addition of <jats:italic>Trp53<\/jats:italic> deficiency. Herein, we report the creation and characterization of a novel <jats:italic>Brca1<\/jats:italic> mutant rat model harboring the germline L63X mutation, which mimics a founder mutation in Japan, through CRISPR\u2010Cas9\u2013based genome editing. Homozygotes (<jats:italic>Brca1<\/jats:italic><jats:sup>L63X\/L63X<\/jats:sup>) were embryonic lethal, whereas heterozygotes (<jats:italic>Brca1<\/jats:italic><jats:sup>L63X\/+<\/jats:sup>) showed apparently normal development. Without carcinogen exposure, heterozygotes developed mammary carcinoma at a comparable incidence rate with their wild\u2010type (WT) littermates during their lifetime. Intraperitoneal injection of 1\u2010methyl\u20101\u2010nitrosourea (25 or 50\u2009mg\/kg) at 7\u2009weeks of age induced mammary carcinogenesis at comparable levels among the heterozygotes and their littermates. After exposure to ionizing radiation (0.1\u20132\u00a0Gy) at 7\u2009weeks of age, the heterozygotes, but not WT littermates, displayed dose\u2010dependent mammary carcinogenesis with 0.8\u00a0Gy<jats:sup>\u22121<\/jats:sup> excess in hazard ratio during their middle age; the relative susceptibility of the heterozygotes was more prominent when rats were irradiated at 3\u2009weeks of age. The heterozygotes had tumors with a lower estrogen receptor \u03b1 immunopositivity and no evidence of somatic mutations of the WT allele. The <jats:italic>Brca1<\/jats:italic><jats:sup>L63X\/+<\/jats:sup> rats thus offer the first single\u2010mutation, heterozygous model of <jats:italic>BRCA1<\/jats:italic>\u2010associated breast cancer, especially with exposure to a DNA break\u2010inducing carcinogen. This implies that such carcinogens are causative and a key to breast cancer prevention in individuals who carry high\u2010risk <jats:italic>BRCA1<\/jats:italic> mutations.<\/jats:p>","DOI":"10.1111\/cas.15485","type":"journal-article","created":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T09:34:01Z","timestamp":1658223241000},"page":"3362-3375","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["<scp><i>Brca1<\/i><sup>L63X<\/sup><\/scp><sup>\/+<\/sup> rat is a novel model of human <i>BRCA1<\/i> deficiency displaying susceptibility to radiation\u2010induced mammary cancer"],"prefix":"10.1111","volume":"113","author":[{"given":"Yuzuki","family":"Nakamura","sequence":"first","affiliation":[{"name":"Department of Radiation Effects Research, National Institute of Radiological Sciences, Quantum Life and Medical Science Directorate National Institutes for Quantum Science and Technology  Chiba 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National Institute of Radiological Sciences, Quantum Life and Medical Science Directorate National Institutes for Quantum Science and Technology  Chiba Japan"},{"name":"Department of Radiological Sciences, Graduate School of Human Health Sciences Tokyo Metropolitan University  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazumasa","family":"Inoue","sequence":"additional","affiliation":[{"name":"Department of Radiological Sciences, Graduate School of Human Health Sciences Tokyo Metropolitan University  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Fukushi","sequence":"additional","affiliation":[{"name":"Department of Radiological Sciences, Graduate School of Human Health Sciences Tokyo Metropolitan University  Tokyo 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