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Untangling the ATR-CHEK1 network for prognostication, prediction and therapeutic target validation in breast cancer

Abdel-Fatah, Tarek M.A.; Middleton, Fiona K.; Arora, Arvind; Agarwal, Devika; Chen, Tao; Moseley, Paul M.; Perry, Christina; Doherty, Rachel; Chan, Stephen; Green, Andrew R.; Rakha, Emad; Ball, Graham; Ellis, Ian O.; Curtin, Nicola J.; Madhusudan, Srinivasan


Tarek M.A. Abdel-Fatah

Fiona K. Middleton

Arvind Arora

Devika Agarwal

Tao Chen

Paul M. Moseley

Christina Perry

Rachel Doherty

Stephen Chan

Professor of Breast Cancer Pathology

Graham Ball

Nicola J. Curtin


ATR?CHEK1 signalling is critical for genomic stability. ATR?CHEK1 signalling may be deregulated in breast cancer and have prognostic, predictive and therapeutic significance. We investigated ATR, CHEK1 and phosphorylated CHEK1 Ser345 protein (pCHEK1) levels in 1712 breast cancers. ATR and CHEK1 mRNA expression was evaluated in 1950 breast cancers. Pre?clinically, biological consequences of ATR gene knock down or ATR inhibition by the small molecule inhibitor (VE?821) were investigated in MCF7 and MDA?MB?231 breast cancer cell lines and in non?tumorigenic breast epithelial cells (MCF10A). High ATR and high cytoplasmic pCHEK1 levels were significantly associated with higher tumour stage, higher mitotic index, pleomorphism and lymphovascular invasion. In univariate analyses, high ATR and high cytoplasmic pCHEK1 levels were associated with poor breast cancer specific survival (BCSS). In multivariate analysis, high ATR level remains an independent predictor of adverse outcome. At the mRNA level, high CHEK1 remains associated with aggressive phenotypes including lymph node positivity, high grade, Her?2 overexpression, triple negative, aggressive molecular phenotypes and adverse BCSS. Pre?clinically, CHEK1 phosphorylation at serine345 following replication stress was impaired in ATR knock down and in VE?821 treated breast cancer cells. Doxycycline inducible knockdown of ATR suppressed growth, which was restored when ATR was re?expressed. Similarly, VE?821 treatment resulted in a dose dependent suppression of cancer cell growth and survival (MCF7 and MDA?MB?231) but was less toxic in non?tumorigenic breast epithelial cells (MCF10A). We provide evidence that ATR and CHEK1 are promising biomarkers and rational drug targets for personalized therapy in breast cancer.


Abdel-Fatah, T. M., Middleton, F. K., Arora, A., Agarwal, D., Chen, T., Moseley, P. M., …Madhusudan, S. (2015). Untangling the ATR-CHEK1 network for prognostication, prediction and therapeutic target validation in breast cancer. Molecular Oncology, 9(3), 569-585.

Journal Article Type Article
Acceptance Date Oct 28, 2014
Online Publication Date Nov 6, 2014
Publication Date Mar 31, 2015
Deposit Date Oct 17, 2018
Journal Molecular Oncology
Print ISSN 1574-7891
Electronic ISSN 1878-0261
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 9
Issue 3
Pages 569-585
Keywords Molecular medicine; Genetics; Cancer research; General medicine
Public URL
Publisher URL
Additional Information This article is maintained by: Elsevier; Article Title: Untangling the ATR-CHEK1 network for prognostication, prediction and therapeutic target validation in breast cancer; Journal Title: Molecular Oncology; CrossRef DOI link to publisher maintained version:; Content Type: article; Copyright: Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.