Abstract A27: BLM overexpression promotes tumorigenicity in an azoxymethane/dextran sulfate (AOM/DSS) murine model of intestinal cancer

Abstract

Abstract The role of genomic instability in colorectal cancer susceptibility is well established by studies of hereditary non-polyposis colon cancer (HNPCC), its associated disruption of DNA mismatch repair, and other DNA repair deficiencies that predispose to colon cancer. DNA repair deficiency that results in loss of capacity to maintain the genome leads to increased mutation or chromosome instability that in turn increases tumor formation. In some recent experiments using mouse models of cancer, deletion of genomic housekeeping genes promoted tumorigenesis. The Blm gene encodes a RecQ helicase that represses aberrant homologous recombination. Previous experiments using ApcMin/+ mice showed that a heterozygous Blm mutation increased intestinal tumor formation and tumor dysplasia. Conversely, mice over-expressing BLM displayed more than a 50% reduction of intestinal tumor number compared to wild-type controls. In order to isolate the effect of a Blm mutation on tumorigenicity, we used C57Bl/6 mice treated with azoxymethane and dextran sulfate to induce polyp formation. We predicted that mice with homozygous deletion of Blm would show an increase in tumor formation compared to wild-type mice, and transgenic mice over-expressing BLM would display fewer polyps. After treating our mice for 12 weeks and sacrificing them between 155 and 165 days of age, we found that mice with a complete deletion of Blm displayed a decrease in polyp formation compared to wild-type controls (3.0 polyps v. 5.5 polyps, p = 0.004). Transgenic mice over-expressing BLM in this model showed an increase in median polyp formation compared to wild-type controls (8.5 polyps v. 5.5 polyps, p = 0.01). Ongoing experiments will clarify the mechanism by which Blm promotes tumorigenesis in this mouse model of colon cancer. Citation Format: Kenechi Ebede, Michael McIlhatton, William Hankey, Joanna Groden. BLM overexpression promotes tumorigenicity in an azoxymethane/dextran sulfate (AOM/DSS) murine model of intestinal cancer. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A27.