Our study focuses on the design and testing of melanoma-prevention strategies for use in high-risk populations. Individuals who have germline loss-of-function (LOF) mutations at the highly polymorphic MC1R locus are at 4-fold increased risk for melanoma. Much of this increase likely arises from the loss of MC1R-mediated upregulation of antioxidant, DNA repair, pigment synthesis and anti-apoptotic pathways that protect epidermal melanocytes from the mutagenic effects of UV radiation. We have found that the natural product sulforaphane (SF) protects normal human melanocytes in culture from UV-induced apoptosis and oxidative stress in the absence of MC1R stimulation by its ligand α-MSH. This led us to propose that SF might be useful for protecting the skin of human subjects with LOF MC1R mutations from the harmful effects of UV light. We have sequenced MC1R in volunteers both with and without the red hair phenotype that is typical for humans with LOF mutations. Sequencing was necessary in all volunteers because many individuals with heterozygous LOF mutations do not have the signature pigmentary phenotype, but are still at increased (2-fold) risk for melanoma. Shave biopsies were harvested from those with either wild-type MC1R or two LOF alleles. The epidermal tissues were treated ex vivo with UV and/or SF then analyzed histologically and by qPCR. We found that SF ameliorated many of the effects of UV radiation in tissues from donors with LOF MC1R. This study demonstrates the promise of SF as an agent for protection of human skin in individuals with high-risk MC1R genotypes from the harmful effects of UV radiation.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1867. doi:10.1158/1538-7445.AM2011-1867