The armadillo repeat domain of Apc suppresses intestinal tumorigenesis

The adenomatous polyposis coli (APC) gene is known to act as a tumor suppressor gene in both sporadic and hereditary colorectal cancer by negatively regulating WNT signaling. Familial adenomatous polyposis (FAP) patients develop intestinal polyps due to the presence of a single germline mutation in APC. The severity of the FAP phenotype is a function of the position of the APC mutation, indicating a complex role for APC that extends beyond the canonical WNT pathway. APC encodes a large protein with multiple functional domains, including an armadillo repeat domain that has been linked to protein protein interactions. To determine the effect of the armadillo repeat domain on intestinal tumorigenesis, we generated a congenic mouse line (Apc(Delta 242)) carrying a gene trap cassette between exons 7 and 8 of the murine Apc gene. Apc(Delta 242/+) mice express a truncated Apc product lacking the armadillo repeat domain as part of a fusion protein with beta-geo. Expression of the fusion product was confirmed by X-gal staining, ensuring that Apc(Delta 242) is not a null allele. In contrast, Apc(min/+) mice produce a truncated Apc product that contains an intact armadillo repeat domain. On the C57BL/6J background, Apc(Delta 242/+) mice develop more polyps than do Apc(min/+) mice along the entire length of the small intestine; however, polyps were significantly smaller in Apc(Delta 242/+) mice. In addition, polyp multiplicity in Apc(Delta 242/+) mice is affected by polymorphisms between inbred strains. These data suggest that the armadillo repeat domain of the Apc protein suppresses tumor initiation in the murine intestine while also promoting tumor growth.