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In order to model squamous cell carcinoma development  in vivo , researchers have long preferred hairless mouse models such as SKH-1 mice that have traditionally been classified as ‘wild-type’ mice irrespective of the genetic factors underlying their hairless phenotype. The work presented here shows that mutations in the  Hairless  ( Hr ) gene not only result in the hairless phenotype of the SKH-1 and  Hr −/−   mouse lines but also cause aberrant activation of NFκB and its downstream effectors. We show that in the epidermis,  Hr  is an early UVB response gene that regulates NFκB activation and thereby controls cellular responses to irradiation. Therefore, when  Hr  expression is decreased in  Hr  mutant animals there is a corresponding increase in NFκB activity that is augmented by UVB irradiation. This constitutive activation of NFκB in the  Hr  mutant epidermis leads to the stimulation a large variety of downstream effectors including the cell cycle regulators cyclin D1 and cyclin E, the anti-apoptosis protein Bcl-2, and the pro-inflammatory protein Cox-2. Therefore,  Hr  loss results in a state of uncontrolled epidermal proliferation that promotes tumor development, and  Hr  mutant mice should no longer be considered merely hairless 'wild-type' mice. Instead,  Hr  is a crucial UVB response gene and its loss creates a permissive environment that potentiates increased tumorigenesis.

Loss of Hairless Confers Susceptibility to UVB-Induced Tumorigenesis via Disruption of NF-kappaB Signaling