title: KPNA2 is a nuclear export protein that contributes to aberrant localisation of key proteins and poor prognosis of breast cancer.
abstract: BACKGROUND
  It is recognised that modulations of the nuclear import of macromolecules have a role in changing cellular phenotypes and carcinogenesis. We and others have noticed that aberrant subcellular localisation of DNA damage response (DDR) proteins in breast cancer (BC) is associated with loss-of-function phenotype. This study aims to investigate the biological and clinical significance of the nucleocytoplasmic transport protein karyopherin α-2 (KPNA2), and its role in controlling DDR proteins subcellular localisation in BC.
  
  
  METHODS
  A large (n=1494) and well-characterised series of early-stage invasive BC with a long-term follow-up was assessed for KPNA2 protein by using immunohistochemistry.
  
  
  RESULTS
  KPNA2 expression was associated with the subcellular localisation of key DDR proteins that showed cytoplasmic expression including BRCA1, RAD51, SMC6L1, γH2AX, BARD1, UBC9, PIAS1 and CHK1. High level of KPNA2 was associated not only with cytoplasmic localisation of these proteins but also with their low/negative nuclear expression. Positive KPNA2 expression was associated with negative oestrogen receptor and triple-negative phenotype. Survival analysis showed that KPNA2 was associated with poor outcome (P<0.0001), but this effect was not independent of other prognostic variables.
  
  
  CONCLUSIONS
  This study provides further evidence for the complexity of DDR mechanism in BC, and that KNPA2 has a role in the aberrant subcellular localisation of DDR proteins with subsequent impaired function.
authors.affiliation: 1] Department of Histopathology and School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK [2] Ministry of Higher Education, Riyadh, Saudi Arabia.
authors.forename: A T
authors.initials: AT
authors.lastname: Alshareeda
authors.affiliation: 1] Immunology Department, School of Life Sciences, University of Nottingham, Nottingham, UK [2] Medical Microbiology and Immunology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
authors.forename: O H
authors.initials: OH
authors.lastname: Negm
authors.affiliation: Department of Histopathology and School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK.
authors.forename: A R
authors.initials: AR
authors.lastname: Green
authors.affiliation: Department of Histopathology and School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK.
authors.forename: C C
authors.initials: CC
authors.lastname: Nolan
authors.affiliation: Immunology Department, School of Life Sciences, University of Nottingham, Nottingham, UK.
authors.forename: P
authors.initials: P
authors.lastname: Tighe
authors.affiliation: Department of Oncology and School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK.
authors.forename: N
authors.initials: N
authors.lastname: Albarakati
authors.affiliation: Department of Oncology and School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK.
authors.forename: R
authors.initials: R
authors.lastname: Sultana
authors.affiliation: Department of Oncology and School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK.
authors.forename: S
authors.initials: S
authors.lastname: Madhusudan
authors.affiliation: Department of Histopathology and School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK.
authors.forename: I O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: Department of Histopathology and School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK.
authors.forename: E A
authors.initials: EA
authors.lastname: Rakha
mesh_terms: D021581:Active Transport, Cell Nucleus; D019313:BRCA1 Protein / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D000071877:Checkpoint Kinase 1; D015331:Cohort Studies; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D011379:Prognosis; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D051135:Rad51 Recombinase / Q000378:metabolism; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D016019:Survival Analysis; D046888:Tissue Array Analysis; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D028901:alpha Karyopherins / Q000378:metabolism*; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C468783:H2AX protein, human; D006657:Histones; C490630:KPNA2 protein, human; C106529:PIAS1 protein, human; D050828:Protein Inhibitors of Activated STAT; C432932:SMC6 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D025521:Tumor Suppressor Proteins; D028901:alpha Karyopherins; D044763:Ubiquitin-Conjugating Enzymes; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D000098843:Ubiquitin-Conjugating Enzyme UBC9