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

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.

Citation

Savva, C., De Souza, K., Ali, R., Rakha, E. A., Green, A. R., & Madhusudan, S. (2019). Clinicopathological significance of ataxia-telangiectasia-mutated (ATM) kinase and ataxia telangiectasia-mutated and Rad3 related (ATR) kinase in MYC overexpressed breast cancers. Breast Cancer Research and Treatment, 175(1), 105–115. https://doi.org/10.1007/s10549-018-05113-8

• 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
• Contract Date: Dec 20, 2018