Abstract LB-431: C-terminal patched polymorphism alters UVB-induced susceptibility to skin cancer in p53+/−/C57BL/6 and Ptch+/−/SKH-1 mice
Authors: Weng Zhiping , Arumugam Aadithya , Athar Mohammad 
Published: July 2012

Non-melanoma skin cancer (NMSC) is the most common type of human cancer which includes the squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). Genetic factors play a role in determining susceptibility to NMSCs. In this study, we provide evidence that a C-terminal polymorphism (1267N) in Patched gene (Ptch) plays an important role in altering susceptibility to ultraviolet B (UVB) induced skin carcinogenesis. For this study, first we selected a skin tumor resistant C57BL/6 genetic background. We developed p53+/−/C57BL/6 mice carrying homozygous 1267N (−/−), heterozygous (+/−) or wild-type (+/+) Ptch gene. These mice were exposed to UVB (240 mJ/cm2, three times weekly) for 35 weeks. In these animals, UVB-induced gain-of-function mutant p53 drive skin photocarcinogenesis. We observed that mice carrying wild-type Ptch gene developed SCCs, lymphomas, sarcomas, papillomas, and spindle cell carcinomas whereas mice carrying 1267 single nucleotide polymorphism (SNP) developed a different tumor spectrum. While heterozygous SNP mice developed SCCs, papillomas, and spindle cell carcinomas, the homozygous SNP carrying animals developed mainly SCCs and papillomas. Similarly, tumor numbers and tumor burden were also different in these animals. Wild-type Ptch carrying mice had the fewest number of tumors (0.86 ± 0.55/mouse) and had smallest tumor size (23.98±11.91 mm3/mouse). However, homozygous SNP carriers had an average of 5.50±2.33 tumors/mouse and with tumor size of 405.06±208.42 mm3/mouse. Similar effects of SNP were observed on tumor latency and tumor incidence. We also observed that UVB induced a much higher proliferative response in SNP carrying animals while wild-type animals showed a significant higher number of TUNEL positive sunburn cells. Similar results were observed in Ptch+/−/SKH-1 mice carrying 1267 SNP which showed very significant increase in BCC incidence and multiplicity compared to mice carrying wild-type allele. 1267 SNP carrying mice showed reduced association of PTCH with TID1, another tumor suppressor. A splice variant of Tid1, Tid1S was accumulated in these lesions. The mechanism of enhanced BCC susceptibility was found to be mediated by the activation of non-canonical nuclear factor kappa B (NFκB) signaling as enhanced expression and transcriptional activity of Bcl3 were noted in these BCCs. Blocking Bcl3 entry to the nucleolus by employing a decoy peptide blocked proliferation ultimately leading to tumor regression. Tumors treated with the decoy peptide were more sensitive to cyclopamine-mediated tumor regression than tumors treated with control peptide. The remaining un-regressed tumors showed a significant down-regulation of Bcl3 transcriptional target genes, cyclin D1/N-cadherin. Results of mutation analysis in Ptch/p53 genes in tumors and tumor-adjacent skin will also be presented in addition to p63 and Akt signaling pathways.

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 LB-431. doi:10.1158/1538-7445.AM2011-LB-431