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Breast Cancer Research and Treatment

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Open Access 01-05-2019 | Breast Cancer | Preclinical study

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

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

Published in: Breast Cancer Research and Treatment | Issue 1/2019

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 signalling and ATR-mediated signalling are critical for MYC-induced DNA damage response. Whether ATM and ATR expressions 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 expressions 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 < 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 < 0.05).

Conclusions

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

Available only for authorised users

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Title: Clinicopathological significance of ataxia telangiectasia-mutated (ATM) kinase and ataxia telangiectasia-mutated and Rad3-related (ATR) kinase in MYC overexpressed breast cancers
Authors: Constantinos Savva
Karen De Souza
Reem Ali
Emad A. Rakha
Andrew R. Green
Srinivasan Madhusudan
Publication date: 01-05-2019
Publisher: Springer US
Keywords: Breast Cancer
Ataxia Telangiectasia
Breast Cancer
Published in: Breast Cancer Research and Treatment / Issue 1/2019
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-018-05113-8

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Abstract

Purpose

Methods

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