Vitamin D₃ Produced by Skin Exposure to UVR Inhibits Murine Basal Cell Carcinoma Carcinogenesis

The effect of UVR on human basal cell carcinoma (BCC) epidemiology is complex-the incidence rises until approximately 30,000 hours of lifetime sunlight exposure and then plateaus. We hypothesize that UVR has opposing effects on BCC carcinogenesis-stimulatory via mutagenesis and inhibitory via production of hedgehog-inhibiting vitamin D₃ (D₃). We find that UVR exposure of ionizing radiation-treated Ptch1^+/- mice accelerates BCC carcinogenesis in male mice, in which UVR does not produce D₃. By contrast, in female mice, in which UVR does produce D₃, UVR fails to accelerate BCC carcinogenesis, thus mirroring the plateauing in humans. However, if D₃ production is attenuated in female mice by deletion of keratinocyte lathosterol 5-desaturase, then UVR accelerates ionizing radiation-induced BCC carcinogenesis. Congruently, chronic topical application of D₃ inhibits ionizing radiation-induced BCC tumorigenesis. These findings confirm that UVR-induced production of D₃ in keratinocytes significantly restrains murine BCC tumorigenesis and demonstrate the counterintuitive conclusion that UVR has anti-BCC carcinogenic effects that can explain, at least in part, the complex relationship between exposure to UVR and BCC incidence.