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

A bstract : 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.