MYC regulation of glutamine-proline regulatory axis is key in luminal B breast cancer

• Published in: British journal of cancer Vol. 118; no. 2; pp. 258 - 265
• Main Authors: Craze, Madeleine L, Cheung, Hayley, Jewa, Natasha, Coimbra, Nuno D M, Soria, Daniele, El-Ansari, Rokaya, Aleskandarany, Mohammed A, Wai Cheng, Kiu, Diez-Rodriguez, Maria, Nolan, Christopher C, Ellis, Ian O, Rakha, Emad A, Green, Andrew R
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.01.2018
• Subjects: Aldehyde Dehydrogenase - genetics; Aldehyde Dehydrogenase - metabolism; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Carboxylate reductase; Copy number; delta-1-Pyrroline-5-Carboxylate Reductase; Deoxyribonucleic acid; DNA; Epidermal growth factor; ErbB-2 protein; Female; Gene Dosage; Gene Regulatory Networks; Genes, myc; Glutaminase; Glutaminase - genetics; Glutaminase - metabolism; Glutamine; Glutamine - genetics; Glutamine - metabolism; Humans; Metabolism; Molecular Diagnostics; mRNA; Myc protein; Proline; Proline - genetics; Proline - metabolism; Protein expression; Proteins; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Pyrroline Carboxylate Reductases - genetics; Pyrroline Carboxylate Reductases - metabolism; Pyrroline-5-carboxylate reductase; RNA, Messenger - genetics; RNA, Messenger - metabolism; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2017.387

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. 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. 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 oestrogen receptor (ER)+/human epidermal growth factor receptor (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 BC 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). 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.