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Haploinsufficiency of Krüppel-Like Factor 4 Promotes Adenomatous Polyposis Coli–Dependent Intestinal Tumorigenesis

¹ Division of Digestive Diseases, Department of Medicine, and ² Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia; ³ Division of Gastroenterology and Hepatology, Departments of Medicine and ⁴ Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Requests for reprints: Vincent W. Yang, Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, 201 Whitehead Research Building, 615 Michael Street, Atlanta, GA 30033. Phone: 404-727-5638; Fax: 404-727-5767; E-mail: vyang{at}emory.edu.

The zinc finger transcription factor Krüppel-like factor 4 (KLF4) is frequently down-regulated in colorectal cancer. Previous studies showed that the expression of KLF4 was activated by the colorectal cancer tumor suppressor adenomatous polyposis coli (APC) and that KLF4 repressed the Wnt/ß-catenin pathway. Here, we examined whether KLF4 plays a role in modulating intestinal tumorigenesis by comparing the tumor burdens in mice heterozygous for the Apc^Min allele (Apc^Min/+) and those heterozygous for both the Apc^Min and Klf4 alleles (Klf4^+/–/Apc^Min/+). Between 10 and 20 weeks of age, Klf4^+/–/Apc^Min/+ mice developed, on average, 59% more intestinal adenomas than Apc^Min/+ mice (P < 0.0001). Immunohistochemical staining showed that Klf4 protein levels were lower in the normal-appearing intestinal tissues of Klf4^+/–/Apc^Min/+ mice compared with wild-type, Klf4^+/–, or Apc^Min/+ mice. In contrast, the levels of ß-catenin and cyclin D1 were higher in the normal-appearing intestinal tissues of Klf4^+/–/Apc^Min/+ mice compared with the other three genotypes. Klf4 levels were further decreased in adenomas from both Apc^Min/+ and Klf4^+/–/Apc^Min/+ mice compared with their corresponding normal-appearing tissues. Reverse transcription-PCR showed an inverse correlation between adenoma size and Klf4 mRNA levels in both Klf4^+/–/Apc^Min/+ and Apc^Min/+ mice. There was also a progressive loss of heterozygosity of the wild-type Apc allele in adenomas with increasing size from Klf4^+/–/Apc^Min/+ and Apc^Min/+ mice. Results from this study show that KLF4 plays an important role in promoting the development of intestinal adenomas in the presence of Apc^Min mutation. [Cancer Res 2007;67(15):7147–54]

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