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The combined expression of solute carriers is associated with a poor prognosis in highly proliferative ER+ breast cancer

  • Rokaya El-Ansari
  • Madeleine L. Craze
  • Lutfi Alfarsi
  • Daniele Soria
  • Maria Diez-Rodriguez
  • Christopher C. Nolan
  • Ian O. Ellis
  • Emad A. Rakha
  • Andrew R. GreenEmail author
Preclinical Study

Abstract

Purpose

Breast cancer (BC) is a heterogeneous disease characterised by variant biology, metabolic activity, and patient outcome. Glutamine availability for growth and progression of BC is important in several BC subtypes. This study aimed to evaluate the biological and prognostic role of the combined expression of key glutamine transporters, SLC1A5, SLC7A5, and SLC3A2 in BC with emphasis on the intrinsic molecular subtypes.

Methods

SLC1A5, SLC7A5, and SLC3A2 were assessed at the protein level, using immunohistochemistry on tissue microarrays constructed from a large well-characterised BC cohort (n = 2248). Patients were stratified into accredited clusters based on protein expression and correlated with clinicopathological parameters, molecular subtypes, and patient outcome.

Results

Clustering analysis of SLC1A5, SLC7A5, and SLC3A2 identified three clusters low SLCs (SLC1A5−/SLC7A5−/SLC3A2−), high SLC1A5 (SLC1A5+/SLC7A5−/SLC3A2−), and high SLCs (SLC1A5+/SLC7A5+/SLC3A2+) which had distinct correlations to known prognostic factors and patient outcome (p < 0.001). The key regulator of tumour cell metabolism, c-MYC, was significantly expressed in tumours in the high SLC cluster (p < 0.001). When different BC subtypes were considered, the association with the poor outcome was observed in the ER+ high proliferation/luminal B class only (p = 0.003). In multivariate analysis, SLC clusters were independent risk factor for shorter BC-specific survival (p = 0.001).

Conclusion

The co-operative expression of SLC1A5, SLC7A5, and SLC3A2 appears to play a role in the aggressive subclass of ER+ high proliferation/luminal BC, driven by c-MYC, and therefore have the potential to act as therapeutic targets, particularly in synergism.

Keywords

SLC1A5 SLC7A5 SLC3A2 Clusters Breast cancer Prognosis 

Notes

Acknowledgements

We thank the Nottingham Health Science Biobank and Breast Cancer Now Tissue Bank for the provision of tissue samples.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10549_2018_5111_MOESM1_ESM.docx (2.8 mb)
Supplementary material 1 (DOCX 2.781 MB)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Rokaya El-Ansari
    • 1
  • Madeleine L. Craze
    • 1
  • Lutfi Alfarsi
    • 1
  • Daniele Soria
    • 3
  • Maria Diez-Rodriguez
    • 1
  • Christopher C. Nolan
    • 1
  • Ian O. Ellis
    • 1
    • 2
  • Emad A. Rakha
    • 1
    • 2
  • Andrew R. Green
    • 1
    Email author
  1. 1.Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, Nottingham City HospitalUniversity of NottinghamNottinghamUK
  2. 2.Breast InstituteNottingham University Hospitals NHS TrustNottinghamUK
  3. 3.School of Computer Science and EngineeringUniversity of WestminsterLondonUK

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