Adenomatous polyposis coli in cancer and therapeutic implications

Inactivating mutations of the adenomatous polyposis coli (APC) gene and consequential upregulation of the Wnt signaling pathway are critical initiators in the development of colorectal cancer (CRC), the third most common cancer in the United States for both men and women. Emerging evidence suggests APC mutations are also found in gastric, breast and other cancers. The APC gene, located on chromosome 5q, is responsible for negatively regulating the β-catenin/Wnt pathway by creating a destruction complex with Axin/Axin2, GSK-3β, and CK1. In the event of an APC mutation, β-catenin accumulates, translocates to the cell nucleus and increases the transcription of Wnt target genes that have carcinogenic consequences in gastrointestinal epithelial stem cells. A literature review was conducted to highlight carcinogenesis related to APC mutations, as well as preclinical and clinical studies for potential therapies that target steps in inflammatory pathways, including IL-6 transduction, and Wnt pathway signaling regulation. Although a range of molecular targets have been explored in murine models, relatively few pharmacological agents have led to substantial increases in survival for patients with colorectal cancer clinically. This article reviews a range of molecular targets that may be efficacious targets for tumors with APC mutations.