MYC regulation of Glutamine-Proline regulatory axis is key in Luminal B breast cancer

Craze, Madeleine L.; Cheung, Hayley; Jewa, Natasha; Coimbra, Nuno D.M.; Soria, Daniele; El-Ansari, Rokaya; Aleskandarany, Mohammed A.; Cheng, Kiu Wai; Diez-Rodriguez, Maria; Nolan, Christopher C.; Ellis, Ian O.; Rakha, Emad; Green, Andrew R.

Abstract

Background: Altered cellular metabolism is a hallmark of cancer and some are reliant on Glutamine for sustained proliferation and survival. We hypothesise that the Glutamine-Proline regulatory axis has a key role in Breast cancer (BC) in the highly proliferative classes.
Methods: Glutaminase (GLS), pyrroline-5-carboxylate synthetase (ALDH18A1) and pyrroline-5-carboxylate reductase 1 (PYCR1) were assessed at DNA/mRNA/protein levels in large well-characterised cohorts.
Results: Gain of PYCR1 copy number and high PYCR1 mRNA was associated with luminal B tumours. High ALDH18A1 and high GLS protein expression was observed in the ER+/HER2- high proliferation class (Luminal B) compared with ER+/HER2- low proliferation class (Luminal A) (p=0.030 and p=0.022 respectively), however this was not observed with mRNA. Cluster analysis of the Glutamine-Proline regulatory axis genes revealed significant associations with molecular subtypes of breast cancer and patient outcome independent of standard clinicopathological parameters (p=0.012). High protein expression of the Glutamine-Proline enzymes were all associated with high MYC protein in Luminal B tumours only (p<0.001).
Conclusion: We provide comprehensive clinical data indicating that the Glutamine-Proline regulatory axis plays an important role in the aggressive subclass of luminal BC and is therefore a potential therapeutic target.

Citation

Craze, M. L., Cheung, H., Jewa, N., Coimbra, N. D., Soria, D., El-Ansari, R., Aleskandarany, M. A., Cheng, K. W., Diez-Rodriguez, M., Nolan, C. C., Ellis, I. O., Rakha, E., & Green, A. R. (in press). MYC regulation of Glutamine-Proline regulatory axis is key in Luminal B breast cancer. British Journal of Cancer, https://doi.org/10.1038/bjc.2017.387

• Journal Article Type: Article
• Acceptance Date: Oct 4, 2017
• Online Publication Date: Nov 23, 2017
• Deposit Date: Oct 24, 2017
• Publicly Available Date: Nov 23, 2017
• Journal: British Journal of Cancer
• Print ISSN: 0007-0920
• Electronic ISSN: 1532-1827
• Publisher: Cancer Research UK
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1038/bjc.2017.387
• Keywords: metabolism, breast cancer, prognosis, Luminal B, glutamine, proline
• Public URL: https://nottingham-repository.worktribe.com/output/896557
• Publisher URL: https://www.nature.com/articles/bjc2017387
• Contract Date: Oct 24, 2017