Growth retardation, DNA repair defects, and lack of spermatogenesis in BRCA1-deficient mice

BRCA1 is a nuclear phosphoprotein expressed in a broad spectrum of tissues during cell division. The inheritance of a mutant BRCA1 allele dramatically increases a woman's lifetime risk for developing both breast and ovarian c ancers. A number of mouse lines carrying mutations in the Brca1 gene have b een generated, and mice homozygous for these mutations generally die before day 10 of embryonic development. We report here the survival of a small nu mber of mice homozygous for mutations in both the p53 and Brca1 genes, The survival of these mice is likely due to additional unknown mutations or epi genetic effects. Analysis of the Brca1(-/-) p53(-/-) animals indicates that BRCA1 is not required for the development of most organ systems. However, these mice are growth retarded, males are infertile due to meiotic failure, and the mammary gland of the female mouse is underdeveloped. Growth defici ency due to loss of BRCA1 was more thoroughly examined in an analysis of pr imary fibroblast lines obtained from these animals, Like p53(-/-) fibroblas ts, Brca1(-/-) p53(-/-) cells proliferate more rapidly than wild-type cells ; however, a high level of cellular death in these cultures results in redu ced overall growth rates in comparison to p53(-/-) fibroblasts. Brca1(-/-) p53(-/-) fibroblasts are also defective in transcription-coupled repair and display increased sensitivity to DNA-damaging agents. We show, however, th at after continued culture, and perhaps accelerated by the loss of BRCA1 re pair functions, populations of Brca1(-/-) p53(-/-) fibroblasts with increas ed growth rates can be isolated, The increased survival of BRCA1-deficient fibroblasts in the absence of p53, and with the subsequent accumulation of additional growth-promoting changes, may mimic the events that occur during malignant transformation of BRCA1-deficient epithelia.