Impact of the Mdm2 SNP309-G allele on a murine model of colorectal cancer

Abstract

A single-nucleotide polymorphism (SNP) in the promoter of the Mdm2 gene (Mdm2 SNP309-G) results in an increased Mdm2 expression, partial attenuation of the p53 pathway and accelerated tumor development. Clinical case-control studies indicate the Mdm2 SNP309- G allele associates with a significant increase in colorectal cancer (CRC) risk that is heightened in women, but the biological significance of this polymorphism has never been directly evaluated. To examine whether the Mdm2 SNP309- G allele contributes to colorectal cancer, we generated cohorts of mice harboring either the G (minor allelic variant) or T (major allelic variant) allele and treated them with azoxymethane (AOM), a carcinogen that induces sporadic colorectal cancer. Mdm2 SNP309-G/G mice displayed a significant reduction in survival following AOM treatment with more colonic lesions in a wider distribution throughout the lower and upper colon and an attenuated apoptotic response following exposure. AOM did not significantly induce stabilization of wild-type p53 or activate p53 downstream targets following AOM treatment, regardless of the genotype. Instead, Mdm2 SNP309-G/G colons had significant changes in the expression of genes that regulate Mdm2 transcription (ERα and Sp1) as well as downstream targets of Mdm2. Together these results suggest the Mdm2 SNP309- G allele significantly impacts CRC through mechanisms outside the p53 pathway.