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

El Ansari, Rokaya; Craze, Madeleine L.; Alfarsi, Lutfi; Soria, Daniele; Diez- Rodriguez, Maria; Nolan, Christopher C.; Ellis, Ian O.; Rakha, Emad A.; Green, Andrew R.

Authors

Rokaya El Ansari

Madeleine L. Craze

Lutfi Alfarsi

Daniele Soria

Maria Diez- Rodriguez

Christopher C. Nolan

Ian O. Ellis

Emad A. Rakha

Andrew R. Green

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=2,248). 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 less than 0.001). The key regulator of tumour cell metabolism, c-MYC, was significantly expressed in tumours in the High SLCs cluster (p less than0.001). 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 breast cancer 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.

Journal Article Type Article
Publication Date Jan 22, 2019
Print ISSN 0167-6806
Publisher BMC
Peer Reviewed Peer Reviewed
DOI https://doi.org/10.1007/s10549-018-05111-w
Keywords SLC1A5, SLC7A5, SLC3A2, clusters, breast cancer, prognosis
Publisher URL https://link.springer.com/article/10.1007/s10549-018-05111-w

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