The online version of this article (https://doi.org/10.1007/s10549-018-05113-8) contains supplementary material, which is available to authorized users.
Constantinos Savva and Karen De Souza contributed equally to this work.
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.
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.
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).
We conclude that ATR/ATM-directed stratification and personalisation of therapy may be feasible in MYC overexpressed breast cancer.
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Abdel-Fatah TM et al (2014) Clinicopathological significance of ATM-Chk2 expression in sporadic breast cancers: a comprehensive analysis in large cohorts. Neoplasia 16:982–991. https://doi.org/10.1016/j.neo.2014.09.009 CrossRef
Abdel-Fatah TM et al (2015) Untangling the ATR-CHEK1 network for prognostication, prediction and therapeutic target validation in breast cancer. Mol Oncol 9:569–585. https://doi.org/10.1016/j.molonc.2014.10.013 CrossRef
Bretones G et al (2015) Myc and cell cycle control. Biochim Biophys Acta 1849:506–516. https://doi.org/10.1016/j.bbagrm.2014.03.013 CrossRef
Chen Y, Olopade OI (2008) MYC in breast tumor progression. Expert Rev Anticancer Ther 8:1689–1698. https://doi.org/10.1586/14737220.127.116.119 CrossRef
Chen Z et al (2015) Cross-talk between ER and HER2 regulates c-MYC-mediated glutamine metabolism in aromatase inhibitor resistant breast cancer cells. J Steroid Biochem Mol Biol 149:118–127. https://doi.org/10.1016/j.jsbmb.2015.02.004 CrossRef
Choi M et al (2016) ATM mutations in cancer: therapeutic implications. Mol Cancer Ther 15:1781–1791. https://doi.org/10.1158/1535-7163.MCT-15-0945 CrossRef
Clouaire T et al (2017) Taming tricky DSBs: ATM on duty. DNA Repair 56:84–91. https://doi.org/10.1016/j.dnarep.2017.06.010 CrossRef
Dang CV (2012) MYC on the path to cancer. Cell 149:22–35. https://doi.org/10.1016/j.cell.2012.03.003 CrossRef
Fokas E et al. Targeting ATR in DNA damage response and cancer therapeutics. Cancer Treatment Reviews 40:109–117. https://doi.org/10.1016/j.ctrv.2013.03.002
Hoglund A et al (2011) Therapeutic implications for the induced levels of Chk1 in Myc-expressing cancer cells. Clin Cancer Res 17:7067–7079. https://doi.org/10.1158/1078-0432.ccr-11-1198 CrossRef
Holm S (1979) A simple sequentially rejective multiple test procedure. Scand J Stat 1979 6:65–70
Karnitz LM, Zou L (2015) Molecular pathways: targeting ATR in cancer therapy. Clin Cancer Res 21:4780–4785. https://doi.org/10.1158/1078-0432.ccr-15-0479 CrossRef
Miller TW et al (2011) A gene expression signature from human breast cancer cells with acquired hormone independence identifies MYC as a mediator of antiestrogen resistance. Clin Cancer Res 17:2024–2034. https://doi.org/10.1158/1078-0432.ccr-10-2567 CrossRef
Min A et al (2017) AZD6738, a novel oral inhibitor of ATR, induces synthetic lethality with ATM deficiency in gastric cancer cells. Mol Cancer Ther 16:566–577. https://doi.org/10.1158/1535-7163.MCT-16-0378 CrossRef
Shang Y et al (2000) Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell 103:843–852 CrossRef
Soucek L, Evan GI (2010) The ups and downs of Myc biology. Curr Opin Genet Dev 20:91–95. https://doi.org/10.1016/j.gde.2009.11.001 CrossRef
Wolfer A, Ramaswamy S (2011) MYC and metastasis. Cancer Res 71:2034–2037. https://doi.org/10.1158/0008-5472.CAN-10-3776 CrossRef
Zhang Y et al (2016) Targeting radioresistant breast cancer cells by single agent CHK1 inhibitor via enhancing replication stress. Oncotarget 7:34688–34702. https://doi.org/10.18632/oncotarget.9156
- Clinicopathological significance of ataxia telangiectasia-mutated (ATM) kinase and ataxia telangiectasia-mutated and Rad3-related (ATR) kinase in MYC overexpressed breast cancers
Karen De Souza
Emad A. Rakha
Andrew R. Green
- Springer US
Breast Cancer Research and Treatment
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
Neu im Fachgebiet Onkologie
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