title: Rb1 family mutation is sufficient for sarcoma initiation.
abstract: It is thought that genomic instability precipitated by Rb1 pathway loss rapidly triggers additional cancer gene mutations, accounting for rapid tumour onset following Rb1 mutation. However, recent whole-genome sequencing of retinoblastomas demonstrated little genomic instability, but instead suggested rapid epigenetic activation of cancer genes. These results raise the possibility that loss of the Rb1 pathway, which is a hallmark of cancers, might be sufficient for cancer initiation. Yet, mutation of the Rb1 family or inactivation of the Rb1 pathway in primary cells has proven insufficient for tumour initiation. Here we demonstrate that traditional nude mouse assays impose an artificial anoikis and proliferation barrier that prevents Rb1 family mutant fibroblasts from initiating tumours. By circumventing this barrier, we show that primary fibroblasts with only an Rb1 family mutation efficiently form sarcomas in nude mice, and a Ras-ZEB1-Akt pathway then causes transition of these tumours to an invasive phenotype.
authors.affiliation: 1] Molecular Targets Program, James Brown Cancer Center, University of Louisville Health Sciences Center, 529 South Jackson Street, Louisville, Kentucky 40202, USA [2] Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, 301 East Muhammad Ali Boulevard, Louisville, Kentucky 40202, USA [3] Birth Defects Center, University of Louisville Health Sciences Center, 301 East Muhammad Ali Boulevard, Louisville, Kentucky 40202, USA.
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Liu
authors.forename: Ester
authors.initials: E
authors.lastname: Sánchez-Tilló
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Lu
authors.forename: Brian
authors.initials: B
authors.lastname: Clem
authors.forename: Sucheta
authors.initials: S
authors.lastname: Telang
authors.forename: Alfred B
authors.initials: AB
authors.lastname: Jenson
authors.forename: Miriam
authors.initials: M
authors.lastname: Cuatrecasas
authors.forename: Jason
authors.initials: J
authors.lastname: Chesney
authors.forename: Antonio
authors.initials: A
authors.lastname: Postigo
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Dean
mesh_terms: D000818:Animals; D023102:Anoikis; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009361:Neoplasm Invasiveness; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism; D012513:Sarcoma, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000071799:Zinc Finger E-box-Binding Homeobox 1; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D016160:Retinoblastoma Protein; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins