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Nonmelanoma skin cancers (NMSCs) consist of a variety of tumor types including basal cell carcinoma, squamous cell carcinoma, a variety of hair follicle tumors, and sebaceous gland tumors. Genetic alterations that alter the fate of multipotent stem cells are believed to influence NMSC phenotype. We previously generated a transgenic mouse line which constitutively expressed c-myc under the control of the K14 promoter (K14.MYC2). These mice exhibited an increase in size and number of sebaceous glands, suggesting that c-myc diverted multipotential stem cells to a sebaceous lineage. Our goal in the current study was to determine if alterations in the commitment of multipotent stem cells to different cell fates would influence tumor phenotype. To this end, we exposed K14.MYC2 mice to a chemical carcinogenesis protocol and discovered that these mice were predisposed to develop sebaceous adenomas. Our data demonstrate that genetic alterations that alter the fate of multipotent stem cells during embryonic development can markedly influence the phenotype of NMSC that develop following exposure to carcinogens.

The beta-catenin/TCF signaling pathway is essential for the maintenance of epithelial stem cells in the small intestine. c-Myc a downstream target of beta-catenin/TCF (ref. 2), can induce differentiation of epidermal stem cells in vitro. To determine the role of c-Myc in epidermal stem cells in vivo, we have targeted expression of human MYC2 to the hair follicles and the basal layer of mouse epidermis using a keratin 14 vector (K14.MYC2). Adult K14.MYC2 mice gradually lose their hair and develop spontaneous ulcerated lesions due to a severe impairment in wound healing; their keratinocytes show impaired migration in response to wounding. The expression of beta1 integrin, which is preferentially expressed in epidermal stem cells is unusually low in the epidermis of K14.MYC2 mice. Label-retaining analysis to identify epidermal stem cells reveals a 75% reduction in the number of stem cells in 3-month-old K14.MYC2 mice, compared with wildtype mice. We conclude that deregulated expression of c-Myc in stem cells reduces beta1 integrin expression, which is essential to both keratinocyte migration and stem cell maintenance.