A cancer modifier role for parathyroid hormone-related protein

The parathyroid hormone-related protein (PTHrP) gene (Pthlh) maps in the di stal region of mouse chromosome 6 that contains a quantitative trait locus associated with genetic predisposition to skin tumorigenesis. Here, we repo rt a genetic polymorphism located in the osteostatin encoding region of the Pthlh gene and that produces Thr/ Pro PTHrP variants. Pthlh(Thr) and Pthlh (Pro) alleles were significantly linked with resistance and susceptibility to skin carcinogenesis in phenotypically selected Car-R and Car-S outbred m ice. Transfection of human NCI-H520 squamous cell carcinoma cells with the Pthlh(Pro) allele resulted in cells growing in clusters, tending to pile up , and growing at a significantly faster rate in nude mice than non-transfec ted and Pthlh(Thr)-transfected cells. These results point to the role of th e Pthlh gene as a cancer modifier gene in skin tumorigenesis.