title: Shh and p50/Bcl3 signaling crosstalk drives pathogenesis of BCCs in Gorlin syndrome.
abstract: 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.
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA.
authors.forename: Sandeep C
authors.initials: SC
authors.lastname: Chaudhary
authors.affiliation: Department of Dermatology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Xiuwei
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA.
authors.forename: Aadithya
authors.initials: A
authors.lastname: Arumugam
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA.
authors.forename: Changzhao
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA.
authors.forename: Ritesh K
authors.initials: RK
authors.lastname: Srivastava
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Weng
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA.|Present address: Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA 90048, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Arianna L
authors.initials: AL
authors.lastname: Kim
authors.affiliation: Division of Dermatopathology, Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294-4550, USA.
authors.forename: Kristopher
authors.initials: K
authors.lastname: McKay
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Elmets
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
authors.affiliation: Department of Dermatology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Bickers
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Athar
mesh_terms: D000818:Animals; D000081242:B-Cell Lymphoma 3 Protein; D001478:Basal Cell Nevus Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; C000631345:Bcl3 protein, mouse; D053823:Hedgehog Proteins; D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins; C509239:SHH protein, human; C465570:Shh protein, mouse; D014157:Transcription Factors
keywords: Bcl3; NBCCS; Shh; basal cell carcinoma; murine model