A Bioinformatics-Based Strategy Identifies c-Myc and Cdc25A as Candidates for the Apmt 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 Apmt1and Apmt2, and suggest that, at least in certain instances, bioinformatics can be utilized to bypass congenic construction and subsequent mapping in conventional QTL studies.
Footnotes
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↵3 Present address: National University of Singapore, Singapore 117604.
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↵4 Corresponding author.
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E-MAIL Hunterk{at}mail.nih.gov; FAX (301) 435-8963.
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Article and publication are at http://www.genome.org/cgi/doi/10.1101/gr.210502.
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- Received February 26, 2002.
- Accepted April 3, 2002.
- Cold Spring Harbor Laboratory Press