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Haploinsufficiency of Krüppel-Like Factor 5 Rescues the Tumor-Initiating Effect of the Apc^Min Mutation in the Intestine

¹ Division of Digestive Diseases, Department of Medicine, ² Department of Pharmacology, and ³ Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia

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 30322. Phone: 404-727-5638; Fax: 404-727-5767; E-mail: vyang{at}emory.edu.

Key Words: KLF5 • APC • adenomas • colorectal cancer • β-catenin

Inactivation of the tumor suppressor adenomatous polyposis coli, with the resultant activation of β-catenin, is the initiating event in the development of a majority of colorectal cancers. Krüppel-like factor 5 (KLF5), a proproliferative transcription factor, is highly expressed in the proliferating intestinal crypt epithelial cells. To determine whether KLF5 contributes to intestinal adenoma formation, we examined tumor burdens in Apc^Min/+ mice and Apc^Min/+/Klf5^+/– mice. Compared with Apc^Min/+ mice, Apc^Min/+/Klf5^+/– mice had a 96% reduction in the number of intestinal adenomas. Reduced tumorigenicity in the Apc^Min/+/Klf5^+/– mice correlated with reduced levels and nuclear localization of β-catenin as well as reduced expression of two β-catenin targets, cyclin D1 and c-Myc. In vitro studies revealed a physical interaction between KLF5 and β-catenin that enhanced the nuclear localization and transcriptional activity of β-catenin. Thus, KLF5 is necessary for the tumor-initiating activity of β-catenin during intestinal adenoma formation in Apc^Min/+ mice, and reduced expression of KLF5 offsets the tumor-initiating activity of the Apc^Min mutation by reducing the nuclear localization and activity of β-catenin. [Cancer Res 2009;69(10):4125–33]