Dual role of inactivating Lef1 mutations in epidermis: Tumor promotion and specification of tumor type

The NH2 terminus of LEF1 is frequently mutated in human sebaceous tumors. To investigate how this contributes to cancer, we did two-stage chemical carcinogenesis on K14 Delta NLeft transgenic mice, which express NH2-terminally truncated Left in the epidermal basal layer. Transgenic mice developed more tumors, more rapidly than littermate controls, even without exposure to tumor promoter. They developed sebaccous tumors, whereas controls developed squamous cell carcinomas. K14ANLeft epidermis failed to up-regulate p53 and p21 proteins during tumorigenesis or in response to UV irradiation, and this correlated with impaired p14ARF induction. We propose that LEF1 NH2-terminal mutations play a dual role in skin cancer, specifying tumor type by inhibiting Wnt signaling and acting as a tumor promoter by preventing induction of p53.