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Clinicopathological significance of ataxia-telangiectasia-mutated (ATM) kinase and ataxia telangiectasia-mutated and Rad3 related (ATR) kinase in MYC overexpressed breast cancers

Savva, Constantinos; De Souza, Karen; Ali, Reem; Rakha, Emad A.; Green, Andrew R.; Madhusudan, Srinivasan

Clinicopathological significance of ataxia-telangiectasia-mutated (ATM) kinase and ataxia telangiectasia-mutated and Rad3 related (ATR) kinase in MYC overexpressed breast cancers Thumbnail


Authors

Constantinos Savva

Karen De Souza

Reem Ali

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



Abstract

Purpose: MYC transcription factor has critical roles in cell growth, proliferation, metabolism, differentiation, transformation and angiogenesis. MYC overexpression is seen in about 15% of breast cancers and linked to aggressive phenotypes. MYC overexpression also induces oxidative stress and replication stress in cells. ATM and ATR- mediated signalling is critical for MYC induced DNA damage response. Whether ATM and ATR expression influence clinical outcomes in MYC overexpressed breast cancers is unknown.

Methods: We investigated ATM, ATR and MYC at the transcriptional level [Molecular Taxonomy of Breast Cancer International Consortium cohort (n=1950)] and at the protein level in the Nottingham series comprising 1650 breast tumours. We correlated ATM, ATR and MYC expression to clinicopathological features and survival outcomes.

Results: In MYC over expressed tumours, high ATR or low ATM levels were associated with aggressive breast cancer features such as higher tumour grade, de-differentiation, pleomorphism, high mitotic index, high risk Nottingham Prognostic Index, triple negative and basal-like breast cancers (all adjusted p values [less than] 0.05). Tumours with low ATM or high ATR levels in conjunction with MYC overexpression also have worse overall breast cancer-specific survival (BCSS) (p value [less than] 0.05).

Conclusions: We conclude that ATR/ATM directed stratification and personalisation of therapy may be feasible in MYC overexpressed breast cancer.

Journal Article Type Article
Acceptance Date Dec 18, 2018
Online Publication Date Feb 12, 2019
Publication Date 2019-05
Deposit Date Dec 18, 2018
Publicly Available Date Dec 20, 2018
Journal Breast Cancer Research and Treatment
Print ISSN 0167-6806
Electronic ISSN 1573-7217
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 175
Issue 1
Pages 105–115
DOI https://doi.org/10.1007/s10549-018-05113-8
Public URL https://nottingham-repository.worktribe.com/output/1422509
Publisher URL https://link.springer.com/article/10.1007%2Fs10549-018-05113-8
Related Public URLs Journal now published by Springer. https://link.springer.com/journal/10549

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