title: NOTCH pathway inactivation promotes bladder cancer progression.
abstract: NOTCH signaling suppresses tumor growth and proliferation in several types of stratified epithelia. Here, we show that missense mutations in NOTCH1 and NOTCH2 found in human bladder cancers result in loss of function. In murine models, genetic ablation of the NOTCH pathway accelerated bladder tumorigenesis and promoted the formation of squamous cell carcinomas, with areas of mesenchymal features. Using bladder cancer cells, we determined that the NOTCH pathway stabilizes the epithelial phenotype through its effector HES1 and, consequently, loss of NOTCH activity favors the process of epithelial-mesenchymal transition. Evaluation of human bladder cancer samples revealed that tumors with low levels of HES1 present mesenchymal features and are more aggressive. Together, our results indicate that NOTCH serves as a tumor suppressor in the bladder and that loss of this pathway promotes mesenchymal and invasive features.
authors.forename: Antonio
authors.initials: A
authors.lastname: Maraver
authors.forename: Pablo J
authors.initials: PJ
authors.lastname: Fernandez-Marcos
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Cash
authors.forename: Marinela
authors.initials: M
authors.lastname: Mendez-Pertuz
authors.forename: Marta
authors.initials: M
authors.lastname: Dueñas
authors.forename: Paolo
authors.initials: P
authors.lastname: Maietta
authors.forename: Paola
authors.initials: P
authors.lastname: Martinelli
authors.forename: Maribel
authors.initials: M
authors.lastname: Muñoz-Martin
authors.forename: Mónica
authors.initials: M
authors.lastname: Martínez-Fernández
authors.forename: Marta
authors.initials: M
authors.lastname: Cañamero
authors.forename: Giovanna
authors.initials: G
authors.lastname: Roncador
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Martinez-Torrecuadrada
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Grivas
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: de la Pompa
authors.forename: Alfonso
authors.initials: A
authors.lastname: Valencia
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Paramio
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Real
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D000072056:Transcription Factor HES-1; D025521:Tumor Suppressor Proteins; C489734:Hes1 protein, mouse; C497761:NOTCH1 protein, human; C497764:NOTCH2 protein, human; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; C078493:HES1 protein, human