Molecular Diagnostics | Published:

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

British Journal of Cancer volume 118, pages 258265 (23 January 2018) | Download Citation

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.

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References

  1. , , , , , , , , (2005) High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses. Int J Cancer 116(3): 340–3450.

  2. , (2014) Redox control of glutamine utilization in cancer. Cell death & disease 5: e1561.

  3. , , , , , , , (2006) c-Myc phosphorylation is required for cellular response to oxidative stress. Mol Cell 21(4): 509–519.

  4. , , , , , , , (2015) Glutamate enrichment as new diagnostic opportunity in breast cancer. Int J Cancer 136(7): 1619–1628.

  5. , , , , , , (2014) Metabolic characterization of triple negative breast cancer. BMC Cancer 14: 941.

  6. , , , , , , , , , , , , , , , (2013) The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 153(4): 840–854.

  7. , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , (2012) The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486(7403): 346–352.

  8. (2012) MYC on the path to cancer. Cell 149(1): 22–35.

  9. , , , , , , , , , , , , (2017) Human mitochondrial pyrroline-5-carboxylate reductase 1 promotes invasiveness and impacts survival in breast cancers. Carcinogenesis 38: 519–531.

  10. , , , , , , , , , , (2009) c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458(7239): 762–765.

  11. , , , , , , , , , , , (2016) MYC functions are specific in biological subtypes of breast cancer and confers resistance to endocrine therapy in luminal tumours. Br J Cancer 114(8): 917–928.

  12. , , , , , , , , , , , , , , , , , , , (2014) Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther 13(4): 890–901.

  13. , (2011) Hallmarks of cancer: the next generation. Cell 144(5): 646–674.

  14. , , , , , , (2008) Human Delta1-pyrroline-5-carboxylate synthase: function and regulation. Amino Acids 35(4): 665–672.

  15. , , , , , (2010) Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc Natl Acad Sci USA 107(16): 7455–7460.

  16. , , (2015) Disruption of proline synthesis in melanoma inhibits protein production mediated by the GCN2 pathway. Mol Cancer Res 13(10): 1408–1420.

  17. , , , (2013) Expression of glutamine metabolism-related proteins according to molecular subtype of breast cancer. Endocr Relat Cancer 20(3): 339–348.

  18. , , (2008) Proline modulates the intracellular redox environment and protects mammalian cells against oxidative stress. Free Radic Biol Med 44(4): 671–681.

  19. , , , , , , , , , , , , (2016) PYCR1 and PYCR2 interact and collaborate with RRM2B to protect cells from overt oxidative stress. Sci Rep 6: 18846.

  20. , (2013) Molecular pathways: targeting MYC-induced metabolic reprogramming and oncogenic stress in cancer. Clin Cancer Res 19(21): 5835–5841.

  21. , , , , (2015) Proline biosynthesis augments tumor cell growth and aerobic glycolysis: involvement of pyridine nucleotides. Sci Rep 5: 17206.

  22. , , , , , , (2012) Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC. Proc Natl Acad Sci USA 109(23): 8983–8988.

  23. , (2012) Proline dehydrogenase (oxidase) in cancer. BioFactors 38(6): 398–406.

  24. , , , , (2016) The oncogenic transcription factor c-Jun regulates glutaminase expression and sensitizes cells to glutaminase-targeted therapy. Nat Commun 7: 11321.

  25. , , , , , Statistics Subcommittee of the NCIEWGoCD (2005) REporting recommendations for tumour MARKer prognostic studies (REMARK). Br J Cancer 93(4): 387–391.

  26. , , , , , , , (2012) Proline dehydrogenase is essential for proline protection against hydrogen peroxide induced cell death. Free Radic Biol Med 53(5): 1181–1191.

  27. , , (2013) Bridging epigenetics and metabolism: role of non-essential amino acids. Epigenetics 8(3): 231–236.

  28. , , , (2015) Proline metabolism and cancer: emerging links to glutamine and collagen. Curr Opin Clin Nutr Metab Care 18(1): 71–77.

  29. , , , , (1997) A model for p53-induced apoptosis. Nature 389(6648): 300–305.

  30. , , , (2008) Central carbon metabolism in the progression of mammary carcinoma. Breast Cancer Res Treat 110(2): 297–307.

  31. , , , , , , , , , , , , , (2010) A methodology to identify consensus classes from clustering algorithms applied to immunohistochemical data from breast cancer patients. Comput Biol Med 40(3): 318–330.

  32. , , , , , , , , , , (2010) Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer cell 18(3): 207–219.

  33. , , , , , , , , , , (2008) Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA 105(48): 18782–18787.

  34. , (2010) Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci 35(8): 427–433.

  35. , , , , , , (2017) Knockdown of PYCR1 inhibits cell proliferation and colony formation via cell cycle arrest and apoptosis in prostate cancer. Med Oncol 34(2): 27.

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Acknowledgements

We thank the Nottingham Health Science Biobank and Breast Cancer Now Tissue Bank for the provision of tissue samples. We thank the University of Nottingham (Nottingham Life Cycle 6 and Cancer Research Priority Area) for funding.

Author contribution

ARG & MLC conceived and designed study. HC, NJ, NDMC, KWC, MAA, RE-A, MD-R, CCN, IOE, EAR, ARG carried out experiments and collected data. MLC, HC, NJ, KWC, DS, ARG analysed data. All authors were involved in writing the paper and had final approval of the submitted and published versions.

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Affiliations

  1. Academic Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK

    • Madeleine L Craze
    • , Hayley Cheung
    • , Natasha Jewa
    • , Rokaya El-Ansari
    • , Mohammed A Aleskandarany
    • , Kiu Wai Cheng
    • , Maria Diez-Rodriguez
    • , Christopher C Nolan
    • , Ian O Ellis
    • , Emad A Rakha
    •  & Andrew R Green
  2. Department of Pathology, Instituto Português de Oncologia do Porto FG, Porto 4200-072, Portugal

    • Nuno D M Coimbra
  3. Department of Computer Science, University of Westminster, New Cavendish Street, London W1W 6UW, UK

    • Daniele Soria
  4. Department of Cellular Pathology, Nottingham University Hospitals NHS Trust, Hucknall Road, Nottingham NG5 1PB, UK

    • Ian O Ellis
    •  & Emad A Rakha

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Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to Andrew R Green.

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DOI

https://doi.org/10.1038/bjc.2017.387

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