People with pale skin, red hair, freckles and an inability to tan - the 'red hair/fair skin' phenotype - are at highest risk of developing melanoma, compared to all other pigmentation types. Genetically, this phenotype is frequently the product of inactivating polymorphisms in the melanocortin 1 receptor (MC1R) gene. MC1R encodes a cyclic AMP-stimulating G-protein-coupled receptor that controls pigment production. Minimal receptor activity, as in red hair/fair skin polymorphisms, produces the red/yellow pheomelanin pigment, whereas increasing MC1R activity stimulates the production of black/brown eumelanin. Pheomelanin has weak shielding capacity against ultraviolet radiation relative to eumelanin, and has been shown to amplify ultraviolet-A-induced reactive oxygen species. Several observations, however, complicate the assumption that melanoma risk is completely ultraviolet-radiation-dependent. For example, unlike non-melanoma skin cancers, melanoma is not restricted to sun-exposed skin and ultraviolet radiation signature mutations are infrequently oncogenic drivers. Although linkage of melanoma risk to ultraviolet radiation exposure is beyond doubt, ultraviolet-radiation-independent events are likely to have a significant role. Here we introduce a conditional, melanocyte-targeted allele of the most common melanoma oncoprotein, BRAF V600E, into mice carrying an inactivating mutation in the Mc1r gene (these mice have a phenotype analogous to red hair/fair skin humans). We observed a high incidence of invasive melanomas without providing additional gene aberrations or ultraviolet radiation exposure. To investigate the mechanism of ultraviolet-radiation-independent carcinogenesis, we introduced an albino allele, which ablates all pigment production on the Mc1r e/e background. Selective absence of pheomelanin synthesis was protective against melanoma development. In addition, normal Mc1r e/e mouse skin was found to have significantly greater oxidative DNA and lipid damage than albino-Mc1r e/e mouse skin. These data suggest that the pheomelanin pigment pathway produces ultraviolet-radiation-independent carcinogenic contributions to melanomagenesis by a mechanism of oxidative damage. Although protection from ultraviolet radiation remains important, additional strategies may be required for optimal melanoma prevention.
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Acknowledgements We thank T. Kunisada for generously sharing K14-SCF mice and C. L. Evans for help with mouse skin irradiation. We also thank A. P. Codgill for help with primary tumour cell culture and A. Piris for pathology consultation as well as M. Haigis and Z. Abdel-Malik for discussions. This work was supported by the following grants from the National Institutes of Health 5R01 AR043369-16 (D.E.F.), R01-CA101864 (Y.W.) and F30 ES020663-01 (D.M.), as well as support from the Dr Miriam and Sheldon G. Adelson Medical Research Foundation, the US-Israel Binational Science Foundation, and the Melanoma Research Alliance (D.E.F.).