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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.

Original publication

DOI

10.1007/s10549-014-3035-2

Type

Journal article

Journal

Breast cancer research and treatment

Publication Date

07/2014

Volume

146

Pages

309 - 320

Addresses

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

Keywords

Cell Line, Tumor, Humans, Breast Neoplasms, Neoplasm Staging, Prognosis, Tumor Burden, Gene Expression, Catalytic Domain, Middle Aged, Female, DNA-Activated Protein Kinase, Protein Interaction Domains and Motifs, Neoplasm Grading, Biomarkers, Tumor