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

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