title: Checkpoint kinase1 (CHK1) is an important biomarker in breast cancer having a role in chemotherapy response.
abstract: BACKGROUND
  Checkpoint kinase1 (CHK1), which is a key component of DNA-damage-activated checkpoint signalling response, may have a role in breast cancer (BC) pathogenesis and influence response to chemotherapy. This study investigated the clinicopathological significance of phosphorylated CHK1 (pCHK1) protein in BC.
  
  
  METHODS
  pCHK1 protein expression was assessed using immunohistochemistry in a large, well-characterized annotated series of early-stage primary operable invasive BC prepared as tissue microarray (n=1200).
  
  
  RESULTS
  pCHK1 showed nuclear and/or cytoplasmic expression. Tumours with nuclear expression showed positive associations with favourable prognostic features such as lower grade, lower mitotic activity, expression of hormone receptor and lack of expression of KI67 and PI3K (P<0.001). On the other hand, cytoplasmic expression was associated with features of poor prognosis such as higher grade, triple-negative phenotype and expression of KI67, p53, AKT and PI3K. pCHK1 expression showed an association with DNA damage response (ATM, RAD51, BRCA1, KU70/KU80, DNA-PKCα and BARD1) and sumoylation (UBC9 and PIASγ) biomarkers. Subcellular localisation of pCHK1 was associated with the expression of the nuclear transport protein KPNA2. Positive nuclear expression predicted better survival outcome in patients who did not receive chemotherapy in the whole series and in ER-positive tumours. In ER-negative and triple-negative subgroups, nuclear pCHK1 predicted shorter survival in patients who received cyclophosphamide, methotrexate and 5-florouracil chemotherapy.
  
  
  CONCLUSIONS
  Our data suggest that pCHK1 may have prognostic and predictive significance in BC. Subcellular localisation of pCHK1 protein is related to its function.
authors: 1] Breast Cancer Pathology Research Group, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals NHS Trust, City Hospital, Nottingham NG5 1PB, UK [2] Department of Pathology, Faculty of Medicine, Al-Mustansiriya University, Baghdad, Iraq.
authors: M M
authors: MM
authors: Al-Kaabi
authors: 1] Breast Cancer Pathology Research Group, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals NHS Trust, City Hospital, Nottingham NG5 1PB, UK [2] Ministry of Higher Education, Riyadh, Saudi Arabia.
authors: A T
authors: AT
authors: Alshareeda
authors: Breast Cancer Pathology Research Group, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals NHS Trust, City Hospital, Nottingham NG5 1PB, UK.
authors: D A
authors: DA
authors: Jerjees
authors: Breast Cancer Pathology Research Group, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals NHS Trust, City Hospital, Nottingham NG5 1PB, UK.
authors: A A
authors: AA
authors: Muftah
authors: Breast Cancer Pathology Research Group, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals NHS Trust, City Hospital, Nottingham NG5 1PB, UK.
authors: A R
authors: AR
authors: Green
authors: Breast Cancer Pathology Research Group, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals NHS Trust, City Hospital, Nottingham NG5 1PB, UK.
authors: N H
authors: NH
authors: Alsubhi
authors: Breast Cancer Pathology Research Group, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals NHS Trust, City Hospital, Nottingham NG5 1PB, UK.
authors: C C
authors: CC
authors: Nolan
authors: Department of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham and Nottingham University Hospitals NHS Trust, City Hospital, Nottingham NG5 1PB, UK.
authors: S
authors: S
authors: Chan
authors: Department of Radiology, Breast Institute, Nottingham University Hospitals NHS Trust, City Hospital, Nottingham NG5 1PB, UK.
authors: E
authors: E
authors: Cornford
authors: Department of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham and Nottingham University Hospitals NHS Trust, City Hospital, Nottingham NG5 1PB, UK.
authors: S
authors: S
authors: Madhusudan
authors: 1] Breast Cancer Pathology Research Group, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals NHS Trust, City Hospital, Nottingham NG5 1PB, UK [2] Department of Cellular Pathology, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham NG5 1PB, UK.
authors: I O
authors: IO
authors: Ellis
authors: 1] Breast Cancer Pathology Research Group, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals NHS Trust, City Hospital, Nottingham NG5 1PB, UK [2] Department of Cellular Pathology, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham NG5 1PB, UK.
authors: E A
authors: EA
authors: Rakha
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D002467:Cell Nucleus / Q000378:metabolism; D000071877:Checkpoint Kinase 1; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult; D028901:alpha Karyopherins / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C490630:KPNA2 protein, human; D028901:alpha Karyopherins; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1