title: Whole genome in vivo RNAi screening identifies the leukemia inhibitory factor receptor as a novel breast tumor suppressor.
abstract: Cancer is caused by mutations in oncogenes and tumor suppressor genes, resulting in the deregulation of processes fundamental to the normal behavior of cells. The identification and characterization of oncogenes and tumor suppressors has led to new treatment strategies that have significantly improved cancer outcome. The advent of next generation sequencing has allowed the elucidation of the fine structure of cancer genomes, however, the identification of pathogenic changes is complicated by the inherent genomic instability of cancer cells. Therefore, functional approaches for the identification of novel genes involved in the initiation and development of tumors are critical. Here we report the first whole human genome in vivo RNA interference screen to identify functionally important tumor suppressor genes. Using our novel approach, we identify previously validated tumor suppressor genes including TP53 and MNT, as well as several novel candidate tumor suppressor genes including leukemia inhibitory factor receptor (LIFR). We show that LIFR is a key novel tumor suppressor, whose deregulation may drive the transformation of a significant proportion of human breast cancers. These results demonstrate the power of genome wide in vivo RNAi screens as a method for identifying novel genes regulating tumorigenesis.
authors.affiliation: Department of Medicine, School of Medicine, University of Miami, 1501 NW 10th Ave (BRB 701), Miami, FL 33136, USA. eiorns@med.miami.edu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Iorns
authors.forename: Toby M
authors.initials: TM
authors.lastname: Ward
authors.forename: Sonja
authors.initials: S
authors.lastname: Dean
authors.forename: Anna
authors.initials: A
authors.lastname: Jegg
authors.forename: Dafydd
authors.initials: D
authors.lastname: Thomas
authors.forename: Nirupa
authors.initials: N
authors.lastname: Murugaesu
authors.forename: David
authors.initials: D
authors.lastname: Sims
authors.forename: Costas
authors.initials: C
authors.lastname: Mitsopoulos
authors.forename: Kerry
authors.initials: K
authors.lastname: Fenwick
authors.forename: Iwanka
authors.initials: I
authors.lastname: Kozarewa
authors.forename: Cristina
authors.initials: C
authors.lastname: Naceur-Lombarelli
authors.forename: Marketa
authors.initials: M
authors.lastname: Zvelebil
authors.forename: Clare M
authors.initials: CM
authors.lastname: Isacke
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: H James
authors.initials: HJ
authors.lastname: Hnatyszyn
authors.forename: Mark
authors.initials: M
authors.lastname: Pegram
authors.forename: Marc
authors.initials: M
authors.lastname: Lippman
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C507840:LIFR protein, human; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C106465:MNT protein, human; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53