Developmental expression of Brca2 colocalizes with Brca1 and is associated with proliferation and differentiation in...

Germline mutations in the putative tumor suppressor gene, BRCA1, predispose women to dramatically elevated risks of breast cancer, while germline mutations in the structurally unrelated gene, BRCA2, predispose both men and women to breast cancer. Recent studies have suggested an important developmental role for the murine homologue of BRCA1 in the regulation of proliferation and differentiation. At the present time, however, little is known about the developmental role of BRCA2 or the regulation of its expression in vivo. We have determined the spatial and temporal pattern of expression of the murine homologue of BRCA2 during fetal development, in adult tissues, and in the mammary gland during postnatal development. Our results indicate that Brca2 mRNA expression is highest in proliferating cellular compartments, particularly those undergoing differentiation. In the breast, Brca2 expression is developmentally regulated and is induced during puberty and pregnancy and as a result of parity. Surprisingly, in multiple fetal and adult tissues the spatial and temporal pattern of Brca2 mRNA expression is virtually indistinguishable from that of Brca1, despite the fact that these genes display no homology. These observations suggest that Brca2 is involved in the processes of proliferation and differentiation in the mammary gland and other tissues, and that Brca1 and Brca2 mRNA expression may be regulated by similar pathways and stimuli in multiple cell types. Interestingly, however, our analysis reveals that Brca1 and Brca2 expression are differentially regulated during the development of specific endocrine target tissues, such as the testis during spermatogenesis and the breast during pregnancy. In addition, the ratio of mRNA expression in the mammary glands of adult females relative to adult males is significantly greater for Brca1 than for Brca2. These observations imply that Brca1 and Brca2 mRNA expression are differentially regulated by sex hormones. In order to test this hypothesis, we have analyzed the expression of these two breast cancer susceptibility genes in ovariectomized mice treated with 17beta-estradiol and progesterone. Our results demonstrate that the up-regulation of mRNA expression in the breast by ovarian hormones is significantly greater for Brca1 than for Brca2. These observations suggest that the gender-specific differences in phenotype associated with germline mutations in BRCA2 versus BRCA1 may be related to the differential regulation of these genes by sex hormones.