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Background  Both mutational inactivation of the adenomatous polyposis coli ( APC ) tumor suppressor gene and activation of the  KRAS  oncogene are implicated in the pathogenesis of colorectal cancer. Mice harboring a germline  Apc   Min   mutation or intestine-specific expression of the  KRAS   V 12  gene have been developed. Both mouse strains develop spontaneous intestinal tumors, including adenoma and carcinoma, though at a different age. The zinc finger transcription factor Krüppel-like factor 5 (KLF5) has previously been shown to promote proliferation of intestinal epithelial cells and modulate intestinal tumorigenesis. Here we investigated the  in vivo  effect of  Klf5  heterozygosity on the propensity of  Apc   Min  / KRAS   V 12  double transgenic mice to develop intestinal tumors.    Results  At 12 weeks of age,  Apc   Min  / KRAS   V 12  mice had three times as many intestinal tumors as  Apc   Min   mice. This increase in tumor number was reduced by 92% in triple transgenic  Apc   Min  / KRAS   V 12 / Klf5  +/-  mice. The reduction in tumor number in  Apc   Min  / KRAS   V 12 / Klf5  +/-  mice was also statistically significant compared to  Apc   Min   mice alone, with a 75% decrease. Compared with  Apc   Min  / KRAS   V 12 , tumors from both  Apc   Min  / KRAS   V 12 / Klf5  +/-  and  Apc   Min   mice were smaller. In addition, tumors from  Apc   Min   mice were more distally distributed in the intestine as contrasted by the more proximal distribution in  Apc   Min  / KRAS   V 12  and  Apc   Min  / KRAS   V 12 / Klf5  +/-  mice. Klf5 levels in the normal-appearing intestinal mucosa were higher in both  Apc   Min   and  Apc   Min  / KRAS   V 12  mice but were attenuated in  Apc   Min  / KRAS   V 12 / Klf5  +/-  mice. The levels of β-catenin, cyclin D1 and Ki-67 were also reduced in the normal-appearing intestinal mucosa of  Apc   Min  / KRAS   V 12 / Klf5  +/-  mice when compared to  Apc   Min  / KRAS   V 12  mice. Levels of pMek and pErk1/2 were elevated in the normal-appearing mucosa of  Apc   Min  / KRAS   V 12  mice and modestly reduced in Apc Min / KRAS   V 12 / Klf5  +/-  mice. Tumor tissues displayed higher levels of both Klf5 and β-catenin, irrespective of the mouse genotype from which tumors were derived.    Conclusions  Results of the current study confirm the cumulative effect of  Apc  loss and oncogenic  KRAS  activation on intestinal tumorigenesis. The drastic reduction in tumor number and size due to  Klf5  heterozygosity in  Apc   Min  / KRAS   V 12  mice indicate a critical function of KLF5 in modulating intestinal tumor initiation and progression.

Krüppel-like factor 5 is a crucial mediator of intestinal tumorigenesis in mice harboring combined Apc Min and KRASV 12mutations