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 (Brca1L63X/L63X ) were embryonic lethal, whereas heterozygotes (Brca1L63X/+ ) 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 Brca1L63X/+ 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.

• Authors: Yuzuki Nakamura, Jo Kubota, Yukiko Nishimura, Kento Nagata, Mayumi Nishimura, Kazuhiro Daino, Atsuko Ishikawa, Takehito Kaneko, Tomoji Mashimo, Toshiaki Kokubo, Masaru Takabatake, Kazumasa Inoue, Masahiro Fukushi, Masami Arai, Mitsue Saito, Yoshiya Shimada, Shizuko Kakinuma, Tatsuhiko Imaoka
• Journal: Cancer science (Cancer Sci) Vol. 113 Issue 10 Pg. 3362-3375 (Oct 2022) ISSN: 1349-7006 [Electronic] England
• PMID: 35851737 (Publication Type: Journal Article)
• Copyright: © 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• BRCA1 Protein
• BRCA1 protein, human
• Carcinogens
• Estrogen Receptor alpha

Topics

• Animals
• BRCA1 Protein (genetics)
• Breast Neoplasms (genetics)
• Carcinogens
• Cell Transformation, Neoplastic
• Estrogen Receptor alpha (genetics)
• Female
• Germ-Line Mutation
• Humans
• Middle Aged
• Neoplasms, Radiation-Induced (genetics)
• Rats