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Targeting ataxia telangiectasia mutated and Rad3 related kinase (ATR) in PTEN deficient breast cancers for personalized therapy

Al-Subhi, Nouf; Ali, Reem; Abdel-Fatah, Tarek; Moseley, Paul M.; Chan, Stephen Y.T.; Green, Andrew R.; Ellis, Ian O.; Rakha, Emad; Madhusudan, Srinivasan

Targeting ataxia telangiectasia mutated and Rad3 related kinase (ATR) in PTEN deficient breast cancers for personalized therapy Thumbnail


Authors

Nouf Al-Subhi

Reem Ali

Tarek Abdel-Fatah

Paul M. Moseley

Stephen Y.T. Chan

EMAD RAKHA Emad.Rakha@nottingham.ac.uk
Professor of Breast Cancer Pathology



Abstract

Purpose: PTEN, a negative regulator of PI3K signaling, is involved in DNA repair. ATR is a key sensor of DNA damage and replication stress. We evaluated whether ATR signaling has clinical significance and could be targeted by synthetic lethality in PTEN deficient triple negative breast cancer (TNBC).
Methods: PTEN, ATR and pCHK1Ser345 protein level was evaluated in 1650 human breast cancers. ATR blockade by VE-821 was investigated in PTEN-proficient (MDAMB-231) and PTEN-deficient (BT-549, MDA-MB-468) TNBC cell lines. Functional studies included DNA repair expression profiling, MTS cell-proliferation assay, FACS (cell cycle progression & ?H2AX accumulation) and FITC-annexin V flow cytometry analysis.
Results: Low nuclear PTEN was associated with higher grade, pleomorphism, dedifferentiation, higher mitotic index, larger tumour size, ER negativity, and shorter survival (p values

Citation

Al-Subhi, N., Ali, R., Abdel-Fatah, T., Moseley, P. M., Chan, S. Y., Green, A. R., …Madhusudan, S. (2018). Targeting ataxia telangiectasia mutated and Rad3 related kinase (ATR) in PTEN deficient breast cancers for personalized therapy. Breast Cancer Research and Treatment, 169(2), 277–286. https://doi.org/10.1007/s10549-018-4683-4

Journal Article Type Article
Acceptance Date Jan 18, 2018
Online Publication Date Feb 2, 2018
Publication Date 2018-06
Deposit Date Jan 23, 2018
Publicly Available Date Feb 2, 2018
Journal Breast Cancer Research and Treatment
Print ISSN 0167-6806
Electronic ISSN 1573-7217
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 169
Issue 2
Pages 277–286
DOI https://doi.org/10.1007/s10549-018-4683-4
Keywords Breast cancer; biomarker; PTEN; ATR; Triple negative breast cancer; Synthetic lethality
Public URL https://nottingham-repository.worktribe.com/output/908295
Publisher URL https://link.springer.com/article/10.1007%2Fs10549-018-4683-4

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