Spontaneous and Radiation-induced Mammary and Thyroid Tumorigenesis in LEW and (SD×COP)F₁ Brca1 ^L63X/+ Rats

Carriers of germline mutations in BRCA1/2 have an increased risk of carcinogenesis in breast, ovary, pancreas, stomach, etc. We previously established the Brca1 mutant (Brca1 ^L63X/+) rat model on a Sprague-Dawley (SD) background, and it displayed an increased risk of mammary carcinoma during middle age after γ-ray exposure at 7 weeks of age. At younger ages, this model showed no increased risk of mammary tumors or other tumors, probably because of the relatively high susceptibility of the SD background to radiation-induced mammary carcinogenesis. Thus, we established new Brca1 ^L63X/+ rat models on backgrounds with less susceptibility to mammary carcinogenesis and elucidated tumor risk in mammary tissue and other organs.

Female Brca1 ^L63X/+ rats and wild-type (WT) littermates on the LEW background or the F₁ hybrid between Copenhagen and SD [(SD×COP)F₁] were whole-body irradiated with γ rays at age 7 weeks or left non-irradiated. The rats were palpated weekly, and tumors reaching ~2 cm were biopsied and diagnosed. Rats that were identified as having mammary carcinoma or showing general deterioration were autopsied, and mammary tumors and other tissues, including thyroid, were analyzed for pathology.

The incidence of mammary carcinomas was similar between Brca1 ^L63X/+ and WT rats on the LEW or (SD×COP)F₁ background. Non-irradiated Brca1 ^L63X/+ rats on the LEW background had significantly higher prevalence of thyroid tumors than non-irradiated WT rats. WT rats tended to have increased prevalence of thyroid carcinoma after radiation exposure, but the prevalence did not differ between irradiated Brca1 ^L63X/+ and WT rats.

Brca1 ^L63X/+ rats on the LEW and (SD×COP)F₁ backgrounds did not recapitulate the human breast carcinogenesis phenotype. Notably, our findings suggest that a germline mutation in Brca1 increases the prevalence of spontaneous thyroid tumors.