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

El-Ansari, Rokaya; 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.

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.

Citation

El-Ansari, R., El Ansari, R., Craze, M. L., Alfarsi, L., Soria, D., Diez-Rodriguez, M., …Green, A. R. (2019). The combined expression of solute carriers is associated with a poor prognosis in highly proliferative ER+ breast cancer. Breast Cancer Research and Treatment, 175(1), 27-38. https://doi.org/10.1007/s10549-018-05111-w

• Journal Article Type: Article
• Acceptance Date: Dec 17, 2018
• Online Publication Date: Jan 22, 2019
• Publication Date: 2019-05
• Deposit Date: Dec 17, 2018
• Publicly Available Date: Jan 23, 2020
• Journal: Breast Cancer Research and Treatment
• Print ISSN: 0167-6806
• Electronic ISSN: 1573-7217
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 175
• Issue: 1
• Pages: 27-38
• DOI: https://doi.org/10.1007/s10549-018-05111-w
• Keywords: SLC1A5, SLC7A5, SLC3A2, clusters, breast cancer, prognosis
• Public URL: https://nottingham-repository.worktribe.com/output/1419470
• Publisher URL: https://link.springer.com/article/10.1007/s10549-018-05111-w
• Additional Information: Received: 14 December 2018; Accepted: 18 December 2018; First Online: 22 January 2019; : ; : The authors declare that they have no conflict of interest.
• Contract Date: Dec 17, 2018