Lookup NU author(s): Dr Peter Stephens,
Professor Nicola Curtin
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Radiation-induced DNA damage activates the DNA damage response (DDR). DDR up regulation may predict radio-resistance and increase the risk of early local recurrence despite radiotherapy in early stage breast cancers. In 1755 early stage breast cancers, DDR signalling [ATM, ATR, total Ckh1, Chk1 phosphorylated at serine(345) (pChk1), Chk2, p53], base excision repair [PARP1, POL beta, XRCC1, FEN1, SMUG1], non-homologous end joining (Ku70/Ku80, DNA-PKcs) and homologous recombination [RAD51, BRCA1, gamma H2AX, BLM, WRN, RECQL5, PTEN] protein expression was correlated to time to early local recurrence. Pre-clinically, radio-sensitization by inhibition of Chk1 activation by ATR inhibitor (VE-821) and inhibition of Chk1 (V158411) were investigated in MDA-MB-231 (p53 mutant) and MCF-7 (p53 wild-type) breast cancer cells. In the whole cohort, 208/1755 patients (11.9%) developed local recurrence of which 126 (61%) developed local recurrence within 5 years of initiation of primary therapy. Of the 20 markers tested, only pChk1 and p53 significantly associated with early local recurrence (p value = 0.015 and 0.010, respectively). When analysed together, high cytoplasmic pChk1-nuclear pChk1 (p = 0.039), high cytoplasmic pChk1-p53 (p = 0.004) and high nuclear pChk1-p53 (p = 0.029) co-expression remain significantly linked to early local recurrence. In multivariate analysis, cytoplasmic pChk1 level independently predicted early local recurrence (p = 0.025). In patients who received adjuvant local radiotherapy (n = 949), p53 (p = 0.014) and high cytoplasmic pChk1-p53 (p = 0.017) remain associated with early local recurrence. Pre-clinically, radio-sensitisation by VE-821 or V158411 was observed in both MCF-7 and MDA-MB-231 cells and was more pronounced in MCF-7 cells. We conclude that pChk1 is a predictive biomarker of radiotherapy resistance and early local recurrence. (C) 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
Author(s): Alsubhi N, Middleton F, Abdel-Fatah TMA, Stephens P, Doherty R, Arora A, Moseley PM, Chan SYT, Aleskandarany MA, Green AR, Rakha EA, Ellis IO, Martin SG, Curtin NJ, Madhusudan S
Publication type: Article
Publication status: Published
Journal: Molecular Oncology
Print publication date: 01/02/2016
Online publication date: 03/10/2015
Acceptance date: 19/09/2015
ISSN (print): 1574-7891
ISSN (electronic): 1878-0261
Publisher: Elsevier Science Ltd.
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