Chk1 phosphorylated at serine345 is a predictor of early local recurrence and radio-resistance in breast cancer.

Autor: Alsubhi N; Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG51PB, UK., Middleton F; Northern Institute for Cancer Research, School of Clinical & Laboratory Sciences, Newcastle University, Medical School, Newcastle upon Tyne NE2 4HH, UK., Abdel-Fatah TM; Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK., Stephens P; Northern Institute for Cancer Research, School of Clinical & Laboratory Sciences, Newcastle University, Medical School, Newcastle upon Tyne NE2 4HH, UK., Doherty R; Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG51PB, UK., Arora A; Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG51PB, UK., Moseley PM; Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK., Chan SY; Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK., Aleskandarany MA; Department of Pathology, School of Medicine, University of Nottingham, Nottingham NG51PB, UK., Green AR; Department of Pathology, School of Medicine, University of Nottingham, Nottingham NG51PB, UK., Rakha EA; Department of Pathology, School of Medicine, University of Nottingham, Nottingham NG51PB, UK., Ellis IO; Department of Pathology, School of Medicine, University of Nottingham, Nottingham NG51PB, UK., Martin SG; Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG51PB, UK., Curtin NJ; Northern Institute for Cancer Research, School of Clinical & Laboratory Sciences, Newcastle University, Medical School, Newcastle upon Tyne NE2 4HH, UK. Electronic address: nicola.curtin@ncl.ac.uk., Madhusudan S; Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG51PB, UK; Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK. Electronic address: srinivasan.madhusudan@nottingham.ac.uk.
Jazyk: angličtina
Zdroj: Molecular oncology [Mol Oncol] 2016 Feb; Vol. 10 (2), pp. 213-23. Date of Electronic Publication: 2015 Oct 03.
DOI: 10.1016/j.molonc.2015.09.009
Abstrakt: 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, POLβ, XRCC1, FEN1, SMUG1], non-homologous end joining (Ku70/Ku80, DNA-PKcs) and homologous recombination [RAD51, BRCA1, γH2AX, 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.
(Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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