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Genetic Ablation of CCAAT/Enhancer Binding Protein in Epidermis Reveals Its Role in Suppression of Epithelial Tumorigenesis

¹ Cell Signaling and Cancer Group, Department of Environmental and Molecular Toxicology and ² Functional Genomics Program, North Carolina State University, Raleigh, North Carolina and ³ Laboratory of Protein Dynamics and Signaling, National Cancer Institute, Frederick, Maryland

Requests for reprints: Robert C. Smart, Cell Signaling and Cancer Group, Department of Environmental and Molecular Toxicology, North Carolina State University, Campus Box 7633, Raleigh, NC 27695. Phone: 919-515-7245; Fax: 919-515-7169; E-mail: rcsmart{at}ncsu.edu.

CCAAT/enhancer binding protein (C/EBP) is a basic leucine zipper transcription factor that inhibits cell cycle progression and regulates differentiation in various cell types. C/EBP is inactivated by mutation in acute myeloid leukemia (AML) and is considered a human tumor suppressor in AML. Although C/EBP mutations have not been observed in malignancies other than AML, greatly diminished expression of C/EBP occurs in numerous human epithelial cancers including lung, liver, endometrial, skin, and breast, suggesting a possible tumor suppressor function. However, direct evidence for C/EBP as an epithelial tumor suppressor is lacking due to the absence of C/EBP mutations in epithelial tumors and the lethal effect of C/EBP deletion in mouse model systems. To examine the function of C/EBP in epithelial tumor development, an epidermal-specific C/EBP knockout mouse was generated. The epidermal-specific C/EBP knockout mice survived and displayed no detectable abnormalities in epidermal keratinocyte proliferation, differentiation, or apoptosis, showing that C/EBP is dispensable for normal epidermal homeostasis. In spite of this, the epidermal-specific C/EBP knockout mice were highly susceptible to skin tumor development involving oncogenic Ras. These mice displayed decreased tumor latency and striking increases in tumor incidence, multiplicity, growth rate, and the rate of malignant progression. Mice hemizygous for C/EBP displayed an intermediate-enhanced tumor phenotype. Our results suggest that decreased expression of C/EBP contributes to deregulation of tumor cell proliferation. C/EBP had been proposed to block cell cycle progression through inhibition of E2F activity. We observed that C/EBP blocked Ras-induced and epidermal growth factor–induced E2F activity in keratinocytes and also blocked Ras-induced cell transformation and cell cycle progression. Our study shows that C/EBP is dispensable for epidermal homeostasis and provides genetic evidence that C/EBP is a suppressor of epithelial tumorigenesis. [Cancer Res 2007;67(14):6768–76]