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

Abdel-Fatah, TMA, Middleton, FK, Arora, A, Agarwal, D, Chen, T, Moseley, PM, Perry, C, Doherty, R, Chan, S, Green, AR, Rakha, E, Ball, G ORCID: 0000-0001-5828-7129, Ellis, IO, Curtin, NJ and Madhusudan, S, 2015. Untangling the ATR-CHEK1 network for prognostication, prediction and therapeutic target validation in breast cancer. Molecular Oncology, 9 (3), pp. 569-585. ISSN 1574-7891

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Abstract

Background: ATR-Chk1 signalling network is critical for genomic stability. ATR-Chk1 may be deregulated in breast cancer and have prognostic, predictive and therapeutic significance. Patients and methods: We investigated ATR and phosphorylated CHK1Ser345 protein (pChk1) expression in 1712 breast cancers (Nottingham Tenovus series). ATR and Chk1 mRNA were evaluated in 1950 breast cancers (METABRIC cohort). Pre-clinically, biological consequences of ATR gene knockdown or ATR inhibition by small molecule inhibitor (VE-821) were investigated in MCF-7 and MDA-MB-231 breast cancer cell lines and in non-tumorigenic breast epithelial cells (MCF10A). Results: High ATR and high cytoplasmic pChk1 expression was significantly associated with higher tumour stage, higher mitotic index, pleomorphism and lymphovascular invasion. In univariate analysis, high ATR and high cytoplasmic pChk1 protein expression was associated with shorter breast cancer specific survival (BCSS). In multivariate analysis, high ATR remains an independent predictor of adverse outcome. At the mRNA level, high Chk1 remains associated with aggressive phenotypes including lymph node positivity, high grade, Her-2 overexpression, triple-negative phenotype and molecular classes associated with aggressive behaviour and shorter survival.. Pre-clinically, Chk1 phosphorylation at serine 345 following replication stress (induced by gemcitabine or hydroxyurea treatment) was impaired in ATR knockdown 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 had no effect on non-tumorigenic breast epithelial cells (MCF10A). Conclusions: We provides evidence that ATR and Chk1 are promising biomarkers and rational drug target for personalized therapy in breast cancer.

Item Type: Journal article
Publication Title: Molecular Oncology
Creators: Abdel-Fatah, T.M.A., Middleton, F.K., Arora, A., Agarwal, D., Chen, T., Moseley, P.M., Perry, C., Doherty, R., Chan, S., Green, A.R., Rakha, E., Ball, G., Ellis, I.O., Curtin, N.J. and Madhusudan, S.
Publisher: Elsevier
Date: 2015
Volume: 9
Number: 3
ISSN: 1574-7891
Identifiers:
NumberType
10.1016/j.molonc.2014.10.013DOI
Divisions: Schools > School of Science and Technology
Depositing User: Jonathan Gallacher
Date Added: 11 Feb 2016 09:33
Last Modified: 09 Jun 2017 13:59
URI: http://irep.ntu.ac.uk/id/eprint/26931

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