Why has it been so difficult to model hereditary breast cancer in mice? Homozygous loss of either of the known breast-cancer susceptibility genes, Brca1 and Brca2 , is not compatible with life, whereas mice bearing truncation mutations either die or develop lymphomas instead of mammary cancer. In the December issue of Nature Genetics, Jos Jonkers and colleagues describe how they have overcome these problems by developing a conditional knockout of Brca2, using the cre–lox system.

The authors targeted exon 11 of Brca2, which encodes its Rad51-binding BRC repeats. Binding to Rad51 is necessary for Brca2 to carry out its poorly understood function in DNA repair. To generate a tissue-specific conditional mutant, the authors put the cre gene under the control of the keratin 14 (K14) promoter, which is active in stratified epithelia such as those in mammary gland and skin. By crossing K14cre mice with mice carrying the Brca2Δ11 allele, mice were bred in which both Brca2 alleles were mutated in tissues where the K14 promoter is active. Surpsisingly, these mice did not develop tumours any more frequently than wild-type mice.

So what else is needed to tip their apparently normal mammary tissue towards tumour formation? The tumours of women with BRCA2 mutations often show loss of TP53 ; could this situation be reproduced by crossing Brca2 mutant mice with conditional Trp53 knockout mice? The conditional Trp53 knockouts generated by the authors were tumour prone but didn't develop any mammary tumours. In stark contrast, mice that were homozygous for both mutations in epithelia developed tumours of the mammary gland and skin. Mice with just one functional copy of either Brca2 or Trp53 in epithelium also developed tumours, but with a longer latency. In all the mice lacking one Trp53 allele, the second allele was lost in the tumours, but in those lacking two Trp53 alleles, only about half lost the second Brca2 allele.

Loss of both copies of Trp53, then, is necessary for tumour formation in mice lacking Brca2. Another intriguing finding is that there is nothing unique about mammary tissue, as the double knockouts developed tumours in skin. Further experiments will uncover how these two important tumour suppressors normally collaborate to protect against cancer.