Tumor suppressor genes code for proteins that limit cellular proliferation and cancer progression, and are often exploited in cancer therapies. One such tumor suppressor gene, Phosphatase and Tensin homolog deleted from Chromosome Ten (PTEN), mediates cell growth through negative regulation of phosphatidylinositol 3-kinase (PI3K) dependent pathways. PTEN is frequently deleted or mutated in a variety of human cancers. Mice carrying a PTEN transgene (Super-PTEN mice) were found to be resistant to tumor formation, and even small changes in PTEN expression and activity have been shown to influence cancer susceptibility and progression. We hypothesized that PTEN activity can be altered by modifier genes. To determine whether PTEN modifiers are influencing its activity, we are using the Collaborative Cross (CC), a panel of inbred mouse strains that has a similar amount of genetic variation as human populations. In CC-Super-PTEN crosses, we are utilizing an easily measured phenotype of Super-PTEN mice, reduced body weight, to identify CC strains with altered PTEN function. On average, weanlings carrying the PTEN transgene weigh 16% less than their wild type littermates, but this weight difference varies significantly across strains, from no weight reduction to as much as a 29% difference. This distribution of phenotypes has allowed us to use quantitative trait locus (QTL) mapping to identify potential modifiers of PTEN. Through association mapping, we have determined that the loci with the highest LOD scores reside on chromosomes 2, 12, 16, and X, and we are now reviewing genes within those loci to identify candidate modifiers of PTEN. Additionally, we are using several cancer models to determine the effects of said candidate genes and confirm that an altered PTEN weight phenotype correlates with changes in cancer susceptibility and progression. Ultimately, this research will demonstrate the use of the CC mouse panel to identify novel genetic modifiers and improve our understanding of PTEN regulation.
Citation Format: Amanda Lanier, William Barrington, David Threadgill. Identifying genetic modifiers of PTEN using the Collaborative Cross mouse panel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1542. doi:10.1158/1538-7445.AM2017-1542