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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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Abstract

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 < 0.05). The absence of BRCA1, low XRCC1, low SMUG1, low APE1 and low Polβ was also more likely in low DNA-PKcs expressing tumours (ps < 0.05). Low DNA-PKcs protein expression was significantly associated with worse breast cancer-specific survival (BCSS) in univariate and multivariate analysis (ps < 0.01). At the 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.

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Conflict of interest

The authors declare that they have no conflict of interest

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Authors and Affiliations

  1. Department of Oncology, Nottingham University Hospitals, Nottingham, NG5 1PB, UK

    Tarek Abdel-Fatah, Paul Moseley, Nicola Thompson, Stephen Chan & Srinivasan Madhusudan

  2. Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham, NG5 1PB, UK

    Arvind Arora, Christina Perry & Srinivasan Madhusudan

  3. School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham, NG11 8NS, UK

    Devika Agarwal & Graham Ball

  4. Division of Cancer and Stem Cells, Department of Pathology, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham, NG5 1PB, UK

    Andrew R. Green, Emad Rakha & Ian O. Ellis

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  1. Tarek Abdel-Fatah
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  2. Arvind Arora
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  3. Devika Agarwal
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  4. Paul Moseley
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  5. Christina Perry
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Correspondence to Srinivasan Madhusudan.

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Abdel-Fatah, T., Arora, A., Agarwal, D. et al. Adverse prognostic and predictive significance of low DNA-dependent protein kinase catalytic subunit (DNA-PKcs) expression in early-stage breast cancers. Breast Cancer Res Treat 146, 309–320 (2014). https://doi.org/10.1007/s10549-014-3035-2

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  • DOI: https://doi.org/10.1007/s10549-014-3035-2

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