Glutamine-Proline regulatory axis is associated with MYC expression in Luminal B breast cancer


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Andy Green1,Madeleine L. Craze1,Hayley Cheung1,Natasha Jewa1,Nuno D.M. Coimbra2,Daniele Soria3,Rokaya El-Ansari1,Mohammed A. Aleskandarany1,Kiu Wai Cheng1,Maria Diez-Rodriguez1,Christopher C. Nolan1,Ian O. Ellis4,Emad A. Rakha4
1University of Nottingham,2Istituto Portugues do Oncologia do Porta FG,3University of Westminster,4Nottingham University Hospitals NHS Trust

Abstract

Background

Altered cellular metabolism is a hallmark of cancer and some are reliant on Glutamine (Gln) for their sustained proliferation and survival. Breast cancer (BC) comprises a heterogeneous group of tumours in terms of molecular biology and clinical behaviour. We therefore hypothesised that the Gln-Proline (Pro) regulatory axis has a key role in BC particularly the highly proliferative more aggressive classes and could act as potential therapeutic targets.

Method

Glutaminase (GLS), pyrroline-5-carboxylate synthetase (ALDH18A1) and pyrroline-5-carboxylate reductase 1 (PYCR1) were assessed at the DNA, mRNA and protein levels in large and well-characterised cohorts and was correlated with clinicopathological parameters, molecular subtypes, regulation by MYC, and patients’ outcome.

Results

Gain of PYCR1 copy number and high PYCR1 mRNA, but not protein expression, was associated with luminal B tumours and poor patient outcome (p<0.001). High ALDH18A1 mRNA and protein expression predicted poor survival in Luminal B tumours (p=0.041 and p=0.047 respectively). Low GLS mRNA (p=0.049) and protein (p=0.030) expression predicted a worse survival in HER2+ tumours. The Gln-Pro regulatory axis genes were clustered into three clusters which were significantly associated with molecular subtypes of breast cancer and patient outcome independent of standard clinicopathological parameters (p=0.012). High protein expression of the Gln-Pro enzymes were all associated with high MYC protein in Luminal B tumours only (p<0.001).

Conclusion

We provide comprehensive clinical data indicating the Gln-Pro regulatory axis plays an important role in the aggressive subclass of luminal BC and is therefore a potential therapeutic target.