Abstract
PurposeMYC 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.MethodsWe 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.ResultsIn 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).ConclusionsWe conclude that ATR/ATM-directed stratification and personalisation of therapy may be feasible in MYC overexpressed breast cancer.
Highlights
The c-MYC transcription factor has critical roles in cell growth, proliferation, metabolism, differentiation, transformation and angiogenesis
A key substrate of Ataxia telangiectasia-mutated kinase (ATM) is Chk2 whose phosphorylation at Thr68 results in activation and phosphorylation of a several proteins involved in DNA repair, recombination, cell cycle progression and apoptosis [34]
We show that ATM and ATR levels have clinicopathological, predictive and prognostic significance in MYC overexpressed breast cancer
Summary
The c-MYC transcription factor has critical roles in cell growth, proliferation, metabolism, differentiation, transformation and angiogenesis. MYC overexpression has been linked to specific subtypes of aggressive breast cancers [7, 16, 21, 38]. MYC overexpression can promote replication stress in cells [17]. Ataxia telangiectasia-mutated kinase (ATM) and ataxia telangiectasia and Rad3-related kinase (ATR) are critical for c-MYC-induced DNA damage response [18, 24, 32]. Activated ATR in turn phosphorylates Chk at Ser345 and Ser317, as well as several other target proteins involved in DNA repair and cell cycle progression [18, 24, 32]. A key substrate of ATM is Chk whose phosphorylation at Thr results in activation and phosphorylation of a several proteins involved in DNA repair, recombination, cell cycle progression and apoptosis [34]
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