Brca2-null embryonic survival is prolonged on the BALB/c genetic background

Women who inherit mutations in the BRCA2 cancer susceptibility gene have an 85% chance of developing breast cancer. The function of the BRCA2 gene rem ains elusive, but there is evidence to support its role in transcriptional transactivation, tumor suppression, and the maintenance of genomic integrit y. Individuals with identical BRCA2 mutations display a different distribut ion of cancers, suggesting that there are low-penetrance genes that can mod ify disease outcome. We hypothesized that genetic background could influenc e embryonic survival of a Brca2 mutation in mice. Brca2-null embryos with a 129/SvEv genetic background (129(B2-/-)) died before embryonic day 8.5. Tr ansfer of this Brca2 mutation onto the BALB/cJ genetic background (BALB/c(B 2-/-)) extended survival to embryonic day 10.5. These results indicate that the BALB/c background harbors genetic modifiers that can prolong Brca2-nul l embryonic survival. The extended survival of BALB/cB2-/- embryos enabled us to ask whether transcriptional regulation of the Brca1 and Brca2 genes i s interdependent. The interdependence of Brca1 and Brca2 was evaluated by s tudying Brca2 gene expression in BALB/c(B1-/-) embryos and Brca1 gene expre ssion in BALB/c(B2-/-) embryos. Nonisotopic in situ hybridization demonstra ted that Brca2 transcript levels were comparable in BALB/c(B1-/-) embryos a nd wild-type littermates. Likewise, reverse transcriptase-polymerase chain reactions confirmed Brca1 mRNA expression in embryonic day 8.5 BALB/c(B2-/- ) embryos that was comparable to Brca2-heterozygous littermates. Thus, the Brca1 and Brca2 transcripts are expressed independently of one another in B rca1- and Brca2-null embryos. (C) 2000 Wiley-Liss. Inc.