Adverse prognostic and predictive significance of low DNA-dependent protein kinase catalytic subunit (DNA-PKcs) expression in early-stage breast cancers

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• 作者：Tarek Abdel-Fatah (1)
  Arvind Arora (2)
  Devika Agarwal (3)
  Paul Moseley (1)
  Christina Perry (2)
  Nicola Thompson (1)
  Andrew R. Green (4)
  Emad Rakha (4)
  Stephen Chan (1)
  Graham Ball (3)
  Ian O. Ellis (4)
  Srinivasan Madhusudan (1) (2)
  
• 关键词：DNA repair ; DNA ; PKcs ; Breast cancer ; Prognostic factor ; Predictive factor
• 刊名：Breast Cancer Research and Treatment
• 出版年：2014
• 出版时间：July 2014
• 年：2014
• 卷：146
• 期：2
• 页码：309-320
• 全文大小：1,422 KB
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• 作者单位：Tarek Abdel-Fatah (1)
  Arvind Arora (2)
  Devika Agarwal (3)
  Paul Moseley (1)
  Christina Perry (2)
  Nicola Thompson (1)
  Andrew R. Green (4)
  Emad Rakha (4)
  Stephen Chan (1)
  Graham Ball (3)
  Ian O. Ellis (4)
  Srinivasan Madhusudan (1) (2)
  
  1. Department of Oncology, Nottingham University Hospitals, Nottingham, NG5 1PB, UK
  2. Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham, NG5 1PB, UK
  3. School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham, NG11 8NS, UK
  4. Division of Cancer and Stem Cells, Department of Pathology, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham, NG5 1PB, UK
  
• ISSN：1573-7217

文摘

DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a serine threonine kinase belonging to the PIKK family (phosphoinositide 3-kinase-like-family of protein kinase), is a critical component of the non-homologous end-joining pathway required for the repair of DNA double-strand breaks. DNA-PKcs may be involved in breast cancer pathogenesis. We evaluated clinicopathological significance of DNA-PKcs protein expression in 1,161 tumours and DNA-PKcs mRNA expression in 1,950 tumours. We correlated DNA-PKcs to markers of aggressive phenotypes, DNA repair, apoptosis, cell cycle regulation and survival. Low DNA-PKcs protein expression was associated with higher tumour grade, higher mitotic index, tumour de-differentiation and tumour type (ps?BRCA1, low XRCC1, low SMUG1, low APE1 and low Polβ was also more likely in low DNA-PKcs expressing tumours (ps?mRNA level, similarly, low DNA-PKcs was associated with poor BCSS. In patients with ER-positive tumours who received endocrine therapy, low DNA-PKcs (protein and mRNA) was associated with poor survival. In ER-negative patients, low DNA-PKcs mRNA remains significantly associated with adverse outcome. Our study suggests that low DNA-PKcs expression may have prognostic and predictive significance in breast cancers.