A Comprehensive Strategy to Combat Colon Cancer Targeting the Adenomatous Polyposis Coli Tumor Suppressor Gene

Abstract

Somatic cells in the majority of colorectal polyps and cancers contain mutations/deletions in the adenomatous polyposis coli (APC) tumor suppressor gene. APC is involved in normal intestinal development and acts to influence a variety of cellular processes. Loss of APC function leads to intestinal neoplasia in both mice and humans. APC influences expression of specific genes, including the c-Myc oncogene, which functions as a transcriptional activator. Loss of APC function leads to alterations in c-Myc-regulated genes including ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis. A single nucleotide polymorphism (SNP) in the ODC promoter affecting c-Myc-dependent expression has been associated with risk of colorectal and other cancers. Pharmaceuticals that target structural features of the c-Myc promoter, and suppress expression of c-Myc and other genes regulated by similar promoter elements, are being developed as potential colorectal cancer chemotherapies. Difluoromethylornithine (DFMO), a selective inhibitor of ODC, is under clinical evaluation as a colorectal cancer chemopreventive agent. APC and APC-dependent genes, such as c-Myc and ODC, may be useful as genetic markers of risk and as targets for chemoprevention and therapy for colorectal cancer.