Preclinical study

Breast Cancer Research and Treatment

, Volume 135, Issue 1, pp 79-91

First online:

Whole genome in vivo RNAi screening identifies the leukemia inhibitory factor receptor as a novel breast tumor suppressor

  • Elizabeth IornsAffiliated withDepartment of Medicine, School of Medicine, University of Miami Email author 
  • , Toby M. WardAffiliated withDepartment of Medicine, School of Medicine, University of Miami
  • , Sonja DeanAffiliated withDepartment of Medicine, School of Medicine, University of Miami
  • , Anna JeggAffiliated withDepartment of Medicine, School of Medicine, University of Miami
  • , Dafydd ThomasAffiliated withDepartment of Pathology, University of Michigan Cancer Center
  • , Nirupa MurugaesuAffiliated withThe Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research
  • , David SimsAffiliated withThe Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research
  • , Costas MitsopoulosAffiliated withThe Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research
  • , Kerry FenwickAffiliated withThe Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research
    • , Iwanka KozarewaAffiliated withThe Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research
    • , Cristina Naceur-LombarelliAffiliated withThe Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research
    • , Marketa ZvelebilAffiliated withThe Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research
    • , Clare M. IsackeAffiliated withThe Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research
    • , Christopher J. LordAffiliated withThe Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research
    • , Alan AshworthAffiliated withThe Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research
    • , H. James HnatyszynAffiliated withDepartment of Medicine, School of Medicine, University of Miami
    • , Mark PegramAffiliated withDepartment of Medicine, School of Medicine, University of Miami
    • , Marc LippmanAffiliated withDepartment of Medicine, School of Medicine, University of Miami

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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.

Keywords

Leukemia inhibitory factor receptor Tumor suppressor gene In vivo RNA interference screen Breast cancer