Shh and p50/Bcl3 signaling crosstalk drives pathogenesis of BCCs in Gorlin syndrome
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Sandeep C. Chaudhary1,*, Xiuwei Tang3,*, Aadithya Arumugam1, Changzhao Li1, Ritesh K. Srivastava1, Zhiping Weng1, Jianmin Xu1, Xiao Zhang2,6, Arianna L. Kim3, Kristopher McKay4, Craig A. Elmets1, Levy Kopelovich5, David R. Bickers3, Mohammad Athar1
1Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294–0019, USA
2Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL 35294–0019, USA
3Department of Dermatology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA
4Division of Dermatopathology, Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294–4550, USA
5Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
6Present address: Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA 90048, USA
*These authors have contributed equally to this work
Mohammad Athar, e-mail: firstname.lastname@example.org
Keywords: basal cell carcinoma, murine model, NBCCS, Shh, Bcl3
Received: July 20, 2015 Accepted: September 04, 2015 Published: September 15, 2015
Nevoid basal cell carcinoma syndrome (NBCCS) is a rare autosomal dominant disorder that is due, in large measure, to aberrant Shh signaling driven by mutations in the tumor suppressor gene Ptch1. Here, we describe the development of Ptch1+/−/ SKH-1 mice as a novel model of this disease. These animals manifest many features of NBCCS, including developmental anomalies and are remarkably sensitive to both ultraviolet (UVB) and ionizing radiation that drive the development of multiple BCCs. Just as in patients with NBCCS, Ptch1+/−/SKH-1 also spontaneously develops BCCs and other neoplasms such as rhabdomyomas/rhabdomyosarcomas. Administration of smoothened inhibitors (vismodegib/itraconazole/cyclopamine) or non-steroidal anti-inflammatory drug (sulindac/sulfasalazine) each result in partial resolution of BCCs in these animals. However, combined administration of these agents inhibits the growth of UVB-induced BCCs by >90%. Employing small molecule- and decoy-peptide-based approaches we further affirm that complete remission of BCCs could only be achieved by combined inhibition of p50-NFκB/Bcl3 and Shh signaling. We posit that Ptch1+/−/SKH-1 mice are a novel and relevant animal model for NBCCS. Understanding mechanisms that govern genetic predisposition to BCCs should facilitate our ability to identify and treat NBCCS gene carriers, including those at risk for sporadic BCCs while accelerating development of novel therapeutic modalities for these patients.
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