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 D 3 (D 3 ). We find that UVR exposure of ionizing radiation-treated Ptch1 +/– mice accelerates BCC carcinogenesis in male mice, in which UVR does not produce D 3 . By contrast, in female mice, in which UVR does produce D 3 , UVR fails to accelerate BCC carcinogenesis, thus mirroring the plateauing in humans. However, if D 3 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 D 3 inhibits ionizing radiation-induced BCC tumorigenesis. These findings confirm that UVR-induced production of D 3 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.