Abstract
Background
Dysregulated cellular metabolism is one of the hallmarks of cancer with some tumours utilising the glutamine metabolism pathway for their sustained proliferation and survival. Glutamate dehydrogenase (GLUD1) is a key enzyme in glutaminolysis converting glutamate to α-ketoglutarate for entry into the TCA cycle. Breast cancer (BC) comprises a heterogeneous group of tumours in terms of molecular biology and clinical behaviour, and we have previously shown that altered glutamine metabolism varies substantially among the different molecular subtypes. We hypothesise that the prognostic value of GLUD1 expression will differ between the BC molecular subtypes and may act as a potential therapeutic target for BC tumours.
Methods
GLUD1 was assessed at the DNA, mRNA (n = 1980) and protein (n = 1300) levels in large, well-characterised cohorts and correlated with clinicopathological parameters, molecular subtypes, patient outcome, and treatments.
Results
There was a correlation between GLUD1 mRNA and GLUD1 protein expression which were highly expressed in low grade luminal/ER + BC (p < 0.01). GLUD1 mRNA and protein was associated with good patient outcome but not in any specific molecular subtypes. However, high GLUD1 protein expression was associated with a better outcome in triple negative (TN) patients treated with chemotherapy (p = 0.03). High GLUD1 mRNA was associated with the glutamine transporter, SLC1A5, and leucine transporter, SLC7A8 as well as mTOR (p < 0.0001).
Conclusion
We provide comprehensive data indicating GLUD1 plays an important role in luminal/ER + BC. GLUD1 expression predicts a better patient outcome and we show that it has the potential for predicting response to chemotherapy in TNBC patients.
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Acknowledgements
We thank the Nottingham Health Science Biobank and Breast Cancer Now Tissue Bank for the provision of tissue samples. We thank the University of Nottingham (Nottingham Life Cycle 6 and Cancer Research Priority Area) for funding.
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MLC and ARG conceived and designed study. MLC, RE, MAA, KWC, LA, BM, MDR, CCN, IOE, EAR, ARG carried out experiments and collected data. MLC, KWC, ARG analysed data. All authors were involved in writing the paper and had final approval of the submitted and published versions.
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This study was approved by the Nottingham Research Ethics Committee 2 under the title ‘Development of a molecular genetic classification of breast cancer’. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All tissue samples from Nottingham used in this study were pseudo-anonymised and collected prior to 1st September 2006; therefore under the Human Tissue Act informed patient consent was not needed. Release of data was also pseudo-anonymised as per Human Tissue Act regulations. This article does not contain any studies with animals performed by any of the authors.
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Craze, M.L., El-Ansari, R., Aleskandarany, M.A. et al. Glutamate dehydrogenase (GLUD1) expression in breast cancer. Breast Cancer Res Treat 174, 79–91 (2019). https://doi.org/10.1007/s10549-018-5060-z
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DOI: https://doi.org/10.1007/s10549-018-5060-z