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

Abdel-Fatah, T., Arora, A., Agarwal, D., Moseley, P., Perry, C., Thompson, N., Green, A.R., Rakha, E., Chan, S., Ball, G. ORCID: 0000-0001-5828-7129, Ellis, I.O. and 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), pp. 309-320. ISSN 0167-6806

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Abstract

Background: 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 (NHEJ) pathway required for the repair of DNA double strand breaks. DNA-PKcs may be involved in breast cancer pathogenesis. Methods: We evaluated clinicopathological significance of DNA-PKcs protein expression in 1161 tumours and DNA-PKcs mRNA expression in 1950 tumours. We correlated DNA-PKcs to other markers of aggressive phenotypes, DNA repair, apoptosis and cell cycle regulation. Results: Low DNA-PKcs protein expression was associated with higher tumour grade, higher mitotic index, tumour de-differentiation and tumour type (ps<0.05). Absence of BRCA1, low XRCC1/SMUG1/APE1/Polβ were 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 (BCCS) in univariate and multivariate analysis (ps<0.01). At the mRNA level, low DNA-PKcs was associated with PAM50.Her2 and PAM50.LumA molecular phenotypes (ps<0.01) and 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. Conclusions: Our study suggests that low DNA-PKcs expression may have prognostic and predictive significance in breast cancers.

Item Type:	Journal article
Publication Title:	Breast Cancer Research and Treatment
Creators:	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. and Madhusudan, S.
Publisher:	Springer New York LLC
Date:	2014
Volume:	146
Number:	2
ISSN:	0167-6806
Identifiers:	Number Type 10.1007/s10549-014-3035-2 DOI
Divisions:	Schools > School of Science and Technology
Record created by:	Jonathan Gallacher
Date Added:	08 Feb 2016 15:44
Last Modified:	09 Jun 2017 13:59
URI:	https://irep.ntu.ac.uk/id/eprint/26900

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