Abstract
Using a forward genetics approach to map loci in a mouse skin cancer model, we previously identified a genetic locus, Skin tumour modifier of MSM 1 (Stmm1) on chromosome 7, conferring strong tumour resistance. Sub-congenic mapping localized Parathyroid hormone (Pth) in Stmm1b. Here, we report that serum intact-PTH (iPTH) and a genetic polymorphism in Pth are important for skin tumour resistance. We identified higher iPTH levels in sera from cancer-resistant MSM/Ms mice compared with susceptible FVB/NJ mice. Therefore, we performed skin carcinogenesis experiments with MSM-BAC transgenic mice (PthMSM-Tg) and Pth knockout heterozygous mice (Pth+/−). As a result, the higher amounts of iPTH in sera conferred stronger resistance to skin tumours. Furthermore, we found that the coding SNP (rs51104087, Val28Met) localizes in the mouse Pro-PTH encoding region, which is linked to processing efficacy and increased PTH secretion. Finally, we report that PTH increases intracellular calcium in keratinocytes and promotes their terminal differentiation. Taken together, our data suggest that Pth is one of the genes responsible for Stmm1, and serum iPTH could serve as a prevention marker of skin cancer and a target for new therapies.
Highlights
The risk of developing cancer is regulated by a combination of, and interactions between, genetic and environmental factors
parathyroid hormone (Pth)+/− mice were susceptible to chemically induced skin tumours when compared with Pth+/+ mice. These results indicate that Pth haploinsufficiency impacts skin carcinogenesis and high iPTH concentration in sera led to the decrease of papilloma number in mice
We have demonstrated that circulating PTH levels modify the development of chemically induced skin papillomas, and account, at least in part, for the effects of Stmm[1]
Summary
The risk of developing cancer is regulated by a combination of, and interactions between, genetic and environmental factors. The majority of cancer risk has been proposed to be regulated by commonly occurring low penetrance genetic variants, and this has led to a flurry of association studies to compare the frequency of specific variants between cancer patients and normal controls. These studies involve hundreds to tens of thousands of individuals, and yet they continue to be plagued by factors that are difficult to control for such as population heterogeneity, environmental exposure, and weak effects of variants[2,3,4]. The genetic variant in PTH between MSM (i.e. Methionine) and FVB/N (i.e. Valine) occurs at the Pro-PTH region (amino acid position 28), and we demonstrate using in vitro studies that this change influences PTH peptide processing efficacy, with the PthMSM allele having stronger acceleratory intracellular calcium levels, terminal differentiation and inhibitory effects on cell proliferation
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