p27kip1 in intestinal tumorigenesis and chemoprevention in the mouse.

Targeted inactivation of p27(kip1) was sufficient for intestinal tumor formation in mice, but this was strictly a function of diet: tumors formed in p27(+/-) or p27(-/-) mice fed control AIN-76A diet and were increased by a western-style diet but did not develop in mice fed standard chow diet. When crossed with the Apc1638N(+/-) mouse, Apc(+/-),p27(+/-) or Apc(+/-),p27(-/-) mice not only formed twice as many tumors than the sum of the tumors from mutation at either locus alone, but on AIN76A diet also developed intestinal intussusception, a tumor-associated pathology in patients leading to intestinal blockage that has not been reported for intestinal cancer in mouse models. Moreover, the frequency of intussusception was increased when the compound mutant mice were maintained on the western diet, leading to early death. Despite this more aggressive tumor phenotype generated by inactivation of p27 than by inactivation of another cyclin-dependent kinase inhibitor, p21(WAF1/cip1), the nonsteroidal anti-inflammatory drug sulindac was still effective in inhibiting intestinal tumor formation in Apc(+/-),p27(+/-) or Apc(+/-),p27(-/-) mice, which contrasts with the abrogation of the effects of sulindac in Apc(+/-),p21(+/-) or Apc(+/-),p21(-/-) mice, indicating that p27 is not necessary for tumor inhibition by sulindac. Furthermore, tumor inhibition by sulindac was linked to the induction of p21 expression by the drug, regardless of p27 status, leading to suppression of cell proliferation and promotion of cell differentiation and apoptosis in the intestinal mucosa.