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
Karen De Souza
EMAD RAKHA Emad.Rakha@nottingham.ac.uk
Professor of Breast Cancer Pathology
ANDREW GREEN email@example.com
SRINIVASAN MADHUSUDAN firstname.lastname@example.org
Professor of Medical Oncology
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.
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|
|Deposit Date||Dec 18, 2018|
|Publicly Available Date||Dec 20, 2018|
|Journal||Breast Cancer Research and Treatment|
|Peer Reviewed||Peer Reviewed|
|Related Public URLs||Journal now published by Springer. https://link.springer.com/journal/10549|
Clinicopathological significance of ataxia-telegiectasia mutated (ATM) Figure 1
Clinicopathological significance of ataxia-telegiectasia mutated (ATM) Figure 2
Clinicopathological significance of ataxia-telegiectasia mutated (ATM) Supp figure 1
Clinicopathological significance of ataxia-telegiectasia mutated (ATM) Supp figure 2
Clinicopathological significance of ataxia-telegiectasia mutated (ATM) Supp figure 3
Clinicopathological significance of ataxia telangiectasia-mutated (ATM) kinase and ataxia telangiectasia-mutated and Rad3-related (ATR) kinase in MYC overexpressed breast cancers
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