title: Distinct expression profiles of p63 variants during urothelial development and bladder cancer progression.
abstract: The TP63 gene, a member of the TP53 tumor suppressor gene family, can be expressed as at least six isoforms due to alternative promoter use and alternative splicing. The lack of p63 isoform-specific antibodies has limited the analysis of the biological significance of p63. We report a novel set of well-defined antibodies to examine p63 isoforms in mouse and human urothelium during embryogenesis and tumor progression, respectively. We provide evidence that basal and intermediate urothelial cells express p63 isoforms, with the TAp63 variant the first to be detected during development, whereas umbrella cells are characterized by a p63-negative phenotype. Notably, we report that p63-null mice develop a bladder with an abnormal urothelium, constituted by a single layer of cells that express uroplakin II and low molecular weight cytokeratins, consistent with an umbrella cell phenotype. Finally, analysis of 202 human bladder carcinomas revealed a new categorization of invasive tumors into basal-like (positive for ΔNp63 and high molecular weight cytokeratins and negative for low molecular weight cytokeratins) versus luminal-like (negative for ΔNp63 and high molecular weight cytokeratins and positive for low molecular weight cytokeratins) phenotypes, with ΔNp63 expression associated with an aggressive clinical course and poor prognosis. This study highlights the relevance of p63 isoforms in both urothelial development and bladder carcinoma progression, with ΔNp63 acting as an oncogene in certain invasive bladder tumors.
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
authors.forename: Orit
authors.initials: O
authors.lastname: Karni-Schmidt
authors.forename: Mireia
authors.initials: M
authors.lastname: Castillo-Martin
authors.forename: Tian Huai
authors.initials: TH
authors.lastname: Shen
authors.forename: Tian
authors.initials: T
authors.lastname: HuaiShen
authors.forename: Nataliya
authors.initials: N
authors.lastname: Gladoun
authors.forename: Josep
authors.initials: J
authors.lastname: Domingo-Domenech
authors.forename: Marta
authors.initials: M
authors.lastname: Sanchez-Carbayo
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Li
authors.forename: Scott
authors.initials: S
authors.lastname: Lowe
authors.forename: Carol
authors.initials: C
authors.lastname: Prives
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
mesh_terms: D000818:Animals; D000918:Antibody Specificity / Q000276:immunology; D045744:Cell Line, Tumor; D018450:Disease Progression; D006801:Humans; D051379:Mice; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010641:Phenotype; D010750:Phosphoproteins / Q000172:deficiency / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D015203:Reproducibility of Results; D015534:Trans-Activators / Q000172:deficiency / Q000378:metabolism*; D014157:Transcription Factors; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology*; D019459:Urothelium / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism* / Q000473:pathology
chemical_list: D050505:Mutant Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C486419:Trp63 protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins