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

Abstract

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.

• Authors: Nouf Alsubhi, Fiona Middleton, Tarek M A Abdel-Fatah, Peter Stephens, Rachel Doherty, Arvind Arora, Paul M Moseley, Stephen Y T Chan, Mohammed A Aleskandarany, Andrew R Green, Emad A Rakha, Ian O Ellis, Stewart G Martin, Nicola J Curtin, Srinivasan Madhusudan
• Journal: Molecular oncology (Mol Oncol) Vol. 10 Issue 2 Pg. 213-23 (Feb 2016) ISSN: 1878-0261 [Electronic] United States
• PMID: 26459098 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Chemical References

• 3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide
• DNA-Binding Proteins
• Indoles
• Pyrazines
• Pyridones
• RNA, Small Interfering
• Sulfones
• V158411
• Serine
• Protein Kinases
• ATR protein, human
• Ataxia Telangiectasia Mutated Proteins
• CHEK1 protein, human
• Checkpoint Kinase 1

Topics

• Ataxia Telangiectasia Mutated Proteins (antagonists & inhibitors, metabolism)
• Breast Neoplasms (metabolism, radiotherapy, therapy)
• Checkpoint Kinase 1
• Cohort Studies
• DNA Repair
• DNA-Binding Proteins (metabolism)
• Female
• Gene Knockdown Techniques
• Humans
• Indoles (pharmacology)
• MCF-7 Cells
• Neoplasm Recurrence, Local (metabolism, radiotherapy, therapy)
• Neoplasm Staging
• Phosphorylation
• Protein Kinases (chemistry, genetics, metabolism)
• Pyrazines (pharmacology)
• Pyridones (pharmacology)
• RNA Interference
• RNA, Small Interfering (genetics)
• Radiation Tolerance
• Serine (chemistry)
• Sulfones (pharmacology)
• Up-Regulation