Abstract
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. 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. 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). 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.
Highlights
Dysregulated tumour metabolism is an important step in oncogenesis and is acknowledged as one of the revised hallmarks of cancer, whereby cancer cells are able to modify and re-programme their metabolism to most effectively provide the energy required for proliferation and survival [1].One of the most well described metabolic changes in tumour cells is the Warburg effect where glycolysis is utilised to support the increased energy requirement for the rapid growth of tumour cells, even in the presence of oxygen [2]
There was a correlation between GLUD1 mRNA and GLUD1 protein expression which were highly expressed in low grade Luminal/ER+ Breast cancer (BC) (p
High GLUD1 protein expression was associated with a better outcome in triple negative (TN) patients treated with chemotherapy (p=0.03)
Summary
Dysregulated tumour metabolism is an important step in oncogenesis and is acknowledged as one of the revised hallmarks of cancer, whereby cancer cells are able to modify and re-programme their metabolism to most effectively provide the energy required for proliferation and survival [1]. One of the most well described metabolic changes in tumour cells is the Warburg effect where glycolysis is utilised to support the increased energy requirement for the rapid growth of tumour cells, even in the presence of oxygen [2]. Glutaminolysis is proving to be an essential metabolic pathway where the amino acid glutamine (Gln) is used to sustain proliferation and survival [3]. Many tumour cells undergo metabolic re-programming which makes them highly dependable upon this amino acid, and glutamine deprivation results in growth arrest and cell death [4]. Differences in metabolic profiles have been shown to discriminate between oestrogen receptor positive (ER+) and triple negative breast cancers (TNBC) [8], whereby TNBCs have an increased expression of metabolic enzymes involved in glutaminolysis and ER+ BCs which have the lowest level of these enzymes [9, 10]
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