Genetic screen for chromosome instability in mice: Mcm4 and breast cancer.

We recently isolated a hypomorphic mutation of Mcm4 in a phenotype-based screen for chromosome instability in mice. This mutation, named Chaos3 (chromosome aberrations occurring spontaneously 3), causes exclusively mammary adenocarcinomas in approximately 80% of homozygous females. Mcm4 encodes a subunit of the MCM2-7 complex, the replication-licensing factor and the replicative helicase. The Mcm4(Chaos3) mutation appears to destabilize the MCM2-7 complex, causing impaired DNA replication. These findings demonstrate, for the first time, the causative role of an Mcm mutation in cancer development. Furthermore, this raises the possibility that hypomorphic mutations in MCM2-7 genes may increase breast cancer risk in humans.