Brca1L63X /+ rat is a novel model of human BRCA1 deficiency displaying susceptibility to radiation-induced mammary cancer.

Abstract

Women who are heterozygous for deleterious BRCA1 germline mutations harbor a high risk of hereditary breast cancer. Previous Brca1‐heterozygous animal models do not recapitulate the breast cancer phenotype, and thus all currently used knockout models adopt conditional, mammary‐specific homozygous Brca1 loss or addition of Trp53 deficiency. Herein, we report the creation and characterization of a novel Brca1 mutant rat model harboring the germline L63X mutation, which mimics a founder mutation in Japan, through CRISPR‐Cas9–based genome editing. Homozygotes (Brca1 L63X/L63X) were embryonic lethal, whereas heterozygotes (Brca1 L63X/+) showed apparently normal development. Without carcinogen exposure, heterozygotes developed mammary carcinoma at a comparable incidence rate with their wild‐type (WT) littermates during their lifetime. Intraperitoneal injection of 1‐methyl‐1‐nitrosourea (25 or 50 mg/kg) at 7 weeks of age induced mammary carcinogenesis at comparable levels among the heterozygotes and their littermates. After exposure to ionizing radiation (0.1–2 Gy) at 7 weeks of age, the heterozygotes, but not WT littermates, displayed dose‐dependent mammary carcinogenesis with 0.8 Gy−1 excess in hazard ratio during their middle age; the relative susceptibility of the heterozygotes was more prominent when rats were irradiated at 3 weeks of age. The heterozygotes had tumors with a lower estrogen receptor α immunopositivity and no evidence of somatic mutations of the WT allele. The Brca1 L63X/+ rats thus offer the first single‐mutation, heterozygous model of BRCA1‐associated breast cancer, especially with exposure to a DNA break‐inducing carcinogen. This implies that such carcinogens are causative and a key to breast cancer prevention in individuals who carry high‐risk BRCA1 mutations.