Tarek Abdel-Fatah
Adverse prognostic and predictive significance of low DNA-dependent protein kinase catalytic subunit (DNA-PKcs) expression in early-stage breast cancers
Abdel-Fatah, Tarek; Arora, Arvind; Agarwal, Devika; Moseley, Paul; Perry, Christina; Thompson, Nicola; Green, Andrew R.; Rakha, Emad; Chan, Stephen; Ball, Graham; Ellis, Ian O.; Madhusudan, Srinivasan
Authors
Arvind Arora
Devika Agarwal
Paul Moseley
Christina Perry
Nicola Thompson
Dr Andy Green ANDREW.GREEN@NOTTINGHAM.AC.UK
ASSOCIATE PROFESSOR
Professor EMAD RAKHA Emad.Rakha@nottingham.ac.uk
PROFESSOR OF BREAST CANCER PATHOLOGY
Stephen Chan
Graham Ball
Ian O. Ellis
Professor SRINIVASAN MADHUSUDAN srinivasan.madhusudan@nottingham.ac.uk
PROFESSOR OF MEDICAL ONCOLOGY
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.
Citation
Abdel-Fatah, T., Arora, A., Agarwal, D., Moseley, P., Perry, C., Thompson, N., Green, A. R., Rakha, E., Chan, S., Ball, G., Ellis, I. O., & Madhusudan, S. (2014). Adverse prognostic and predictive significance of low DNA-dependent protein kinase catalytic subunit (DNA-PKcs) expression in early-stage breast cancers. Breast Cancer Research and Treatment, 146(2), 309-320. https://doi.org/10.1007/s10549-014-3035-2
Journal Article Type | Article |
---|---|
Acceptance Date | Jun 10, 2014 |
Online Publication Date | Jun 28, 2014 |
Publication Date | 2014-07 |
Deposit Date | Oct 17, 2018 |
Journal | Breast Cancer Research and Treatment |
Print ISSN | 0167-6806 |
Electronic ISSN | 1573-7217 |
Publisher | Springer Verlag |
Peer Reviewed | Peer Reviewed |
Volume | 146 |
Issue | 2 |
Pages | 309-320 |
DOI | https://doi.org/10.1007/s10549-014-3035-2 |
Public URL | https://nottingham-repository.worktribe.com/output/1172254 |
Publisher URL | https://link.springer.com/article/10.1007%2Fs10549-014-3035-2 |
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