A Bioinformatics-Based Strategy Identifies c-<i>Myc</i> and <i>Cdc25A</i> as Candidates for the <i>Apmt</i> Mammary Tumor Latency Modifiers

Abstract

The epistatically interacting modifier loci ( Apmt1 and Apmt2 ) accelerate the polyoma Middle-T (PyVT)-induced mammary tumor. To identify potential candidate genes loci, a combined bioinformatics and genomics strategy was used. On the basis of the assumption that the loci were functioning in the same or intersecting pathways, a search of the literature databases was performed to identify molecular pathways containing genes from both candidate intervals. Among the genes identified by this method were the cell cycle-associated genes Cdc25A and c- Myc , both of which have been implicated in breast cancer. Genomic sequencing revealed noncoding polymorphism in both genes, in the promoter region of Cdc25A , and in the 3′ UTR of c- Myc . Molecular and in vitro analysis showed that the polymorphisms were functionally significant. In vivo analysis was performed by generating compound PyVT/ Myc double-transgenic animals to mimic the hypothetical model, and was found to recapitulate the age-of-onset phenotype. These data suggest that c- Myc and Cdc25A are Apmt1 and Apmt2 , and suggest that, at least in certain instances, bioinformatics can be utilized to bypass congenic construction and subsequent mapping in conventional QTL studies.