Chk1 phosphorylated at serine345 is a predictor of early local recurrence and radio-resistance in breast cancer
Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2016 |
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| Erschienen: |
2016 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
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| Enthalten in: |
Molecular oncology - 10(2016), 2 vom: 12. Feb., Seite 213-23 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Alsubhi, Nouf [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 28.10.2016 Date Revised 18.03.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.molonc.2015.09.009 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Chk1 phosphorylated at serine345 is a predictor of early local recurrence and radio-resistance in breast cancer |
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| 500 | |a Date Revised 18.03.2022 | ||
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| 520 | |a Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Chk1 | |
| 650 | 4 | |a Chk1 inhibitor | |
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| 650 | 4 | |a Radiotherapy | |
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| 650 | 7 | |a Ataxia Telangiectasia Mutated Proteins |2 NLM | |
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| 700 | 1 | |a Middleton, Fiona |e verfasserin |4 aut | |
| 700 | 1 | |a Abdel-Fatah, Tarek M A |e verfasserin |4 aut | |
| 700 | 1 | |a Stephens, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Doherty, Rachel |e verfasserin |4 aut | |
| 700 | 1 | |a Arora, Arvind |e verfasserin |4 aut | |
| 700 | 1 | |a Moseley, Paul M |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Stephen Y T |e verfasserin |4 aut | |
| 700 | 1 | |a Aleskandarany, Mohammed A |e verfasserin |4 aut | |
| 700 | 1 | |a Green, Andrew R |e verfasserin |4 aut | |
| 700 | 1 | |a Rakha, Emad A |e verfasserin |4 aut | |
| 700 | 1 | |a Ellis, Ian O |e verfasserin |4 aut | |
| 700 | 1 | |a Martin, Stewart G |e verfasserin |4 aut | |
| 700 | 1 | |a Curtin, Nicola J |e verfasserin |4 aut | |
| 700 | 1 | |a Madhusudan, Srinivasan |e verfasserin |4 aut | |
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