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

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