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

Br J Cancer. 2018 Jan;118(2):258-265. doi: 10.1038/bjc.2017.387. Epub 2017 Nov 23.

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 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).

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Dehydrogenase / genetics
  • Aldehyde Dehydrogenase / metabolism
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Female
  • Gene Dosage
  • Gene Regulatory Networks
  • Genes, myc
  • Glutaminase / genetics*
  • Glutaminase / metabolism
  • Glutamine / genetics
  • Glutamine / metabolism
  • Humans
  • Proline / genetics*
  • Proline / metabolism
  • Proto-Oncogene Proteins c-myc / genetics*
  • Proto-Oncogene Proteins c-myc / metabolism
  • Pyrroline Carboxylate Reductases / genetics
  • Pyrroline Carboxylate Reductases / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • delta-1-Pyrroline-5-Carboxylate Reductase

Substances

  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • Glutamine
  • Proline
  • ALDH18A1 protein, human
  • Aldehyde Dehydrogenase
  • Pyrroline Carboxylate Reductases
  • Glutaminase