title: In vivo disruption of an Rb-E2F-Ezh2 signaling loop causes bladder cancer.
abstract: Bladder cancer is a highly prevalent human disease in which retinoblastoma (Rb) pathway inactivation and epigenetic alterations are common events. However, the connection between these two processes is still poorly understood. Here, we show that the in vivo inactivation of all Rb family genes in the mouse urothelium is sufficient to initiate bladder cancer development. The characterization of the mouse tumors revealed multiple molecular features of human bladder cancer, including the activation of E2F transcription factor and subsequent Ezh2 expression and the activation of several signaling pathways previously identified as highly relevant in urothelial tumors. These mice represent a genetically defined model for human high-grade superficial bladder cancer. Whole transcriptional characterizations of mouse and human bladder tumors revealed a significant overlap and confirmed the predominant role for Ezh2 in the downregulation of gene expression programs. Importantly, the increased tumor recurrence and progression in human patients with superficial bladder cancer is associated with increased E2F and Ezh2 expression and Ezh2-mediated gene expression repression. Collectively, our studies provide a genetically defined model for human high-grade superficial bladder cancer and demonstrate the existence of an Rb-E2F-Ezh2 axis in bladder whose disruption can promote tumor development.
authors.affiliation: Unidad de Oncología Molecular. CIEMAT (ed70A). Av Complutense 40. 28040 Madrid SPAIN.|Unidad de Oncogenómica. Instituto de Investigación 12 de Octubre i+12, UCM. Av Cordoba s/n. 28041 Madrid SPAIN.
authors.forename: Mirentxu
authors.initials: M
authors.lastname: Santos
authors.affiliation: Unidad de Oncología Molecular. CIEMAT (ed70A). Av Complutense 40. 28040 Madrid SPAIN.|Unidad de Oncogenómica. Instituto de Investigación 12 de Octubre i+12, UCM. Av Cordoba s/n. 28041 Madrid SPAIN.
authors.forename: Mónica
authors.initials: M
authors.lastname: Martínez-Fernández
authors.affiliation: Unidad de Oncología Molecular. CIEMAT (ed70A). Av Complutense 40. 28040 Madrid SPAIN.|Unidad de Oncogenómica. Instituto de Investigación 12 de Octubre i+12, UCM. Av Cordoba s/n. 28041 Madrid SPAIN.
authors.forename: Marta
authors.initials: M
authors.lastname: Dueñas
authors.affiliation: Unidad de Oncología Molecular. CIEMAT (ed70A). Av Complutense 40. 28040 Madrid SPAIN.|Unidad de Oncogenómica. Instituto de Investigación 12 de Octubre i+12, UCM. Av Cordoba s/n. 28041 Madrid SPAIN.
authors.forename: Ramón
authors.initials: R
authors.lastname: García-Escudero
authors.affiliation: Unidad de Oncología Molecular. CIEMAT (ed70A). Av Complutense 40. 28040 Madrid SPAIN.
authors.forename: Begoña
authors.initials: B
authors.lastname: Alfaya
authors.affiliation: Unidad de Uro-Oncología. Hospital Universitario 12 de Octubre. Av Cordoba s/n. 28041 Madrid SPAIN.
authors.forename: Felipe
authors.initials: F
authors.lastname: Villacampa
authors.affiliation: Unidad de Oncología Molecular. CIEMAT (ed70A). Av Complutense 40. 28040 Madrid SPAIN.
authors.forename: Cristina
authors.initials: C
authors.lastname: Saiz-Ladera
authors.affiliation: Unidad de Oncología Molecular. CIEMAT (ed70A). Av Complutense 40. 28040 Madrid SPAIN.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Costa
authors.affiliation: Unidad de Oncogenómica. Instituto de Investigación 12 de Octubre i+12, UCM. Av Cordoba s/n. 28041 Madrid SPAIN.|Unidad de Aplicaciones Biomédicas y Farmacocinética CIEMAT (ed 12). Av Complutense 40. 28040 Madrid SPAIN.
authors.forename: Marta
authors.initials: M
authors.lastname: Oteo
authors.affiliation: Unidad de Uro-Oncología. Hospital Universitario 12 de Octubre. Av Cordoba s/n. 28041 Madrid SPAIN.
authors.forename: José
authors.initials: J
authors.lastname: Duarte
authors.affiliation: Unidad de Uro-Oncología. Hospital Universitario 12 de Octubre. Av Cordoba s/n. 28041 Madrid SPAIN.
authors.forename: Victor
authors.initials: V
authors.lastname: Martínez
authors.affiliation: Unidad de Uro-Oncología. Hospital Universitario 12 de Octubre. Av Cordoba s/n. 28041 Madrid SPAIN.
authors.forename: Mª José
authors.initials: MJ
authors.lastname: Gómez-Rodriguez
authors.affiliation: Unidad de Uro-Oncología. Hospital Universitario 12 de Octubre. Av Cordoba s/n. 28041 Madrid SPAIN.
authors.forename: Mª Luisa
authors.initials: ML
authors.lastname: Martín
authors.affiliation: Unidad de Uro-Oncología. Hospital Universitario 12 de Octubre. Av Cordoba s/n. 28041 Madrid SPAIN.
authors.forename: Manoli
authors.initials: M
authors.lastname: Fernández
authors.affiliation: Departments of Pediatrics and Genetics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Viatour
authors.affiliation: Unidad de Oncogenómica. Instituto de Investigación 12 de Octubre i+12, UCM. Av Cordoba s/n. 28041 Madrid SPAIN.|Unidad de Aplicaciones Biomédicas y Farmacocinética CIEMAT (ed 12). Av Complutense 40. 28040 Madrid SPAIN.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Morcillo
authors.affiliation: Departments of Pediatrics and Genetics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Sage
authors.affiliation: Unidad de Uro-Oncología. Hospital Universitario 12 de Octubre. Av Cordoba s/n. 28041 Madrid SPAIN.
authors.forename: Daniel
authors.initials: D
authors.lastname: Castellano
authors.affiliation: Servicio de Anatomía Patológica. Hospital Universitario 12 de Octubre. Instituto de Investigación 12 de Octubre i+12, UCM. Av Cordoba s/n. 28041 Madrid SPAIN.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Rodriguez-Peralto
authors.affiliation: Unidad de Uro-Oncología. Hospital Universitario 12 de Octubre. Av Cordoba s/n. 28041 Madrid SPAIN.
authors.forename: Federico
authors.initials: F
authors.lastname: de la Rosa
authors.affiliation: Unidad de Oncología Molecular. CIEMAT (ed70A). Av Complutense 40. 28040 Madrid SPAIN.|Unidad de Oncogenómica. Instituto de Investigación 12 de Octubre i+12, UCM. Av Cordoba s/n. 28041 Madrid SPAIN.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Paramio
mesh_terms: D000818:Animals; D018450:Disease Progression; D050684:E2F Transcription Factors / Q000502:physiology*; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000209:etiology; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D059467:Transcriptome; D001749:Urinary Bladder Neoplasms / Q000209:etiology*
chemical_list: D050684:E2F Transcription Factors; D016160:Retinoblastoma Protein; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2