Co-Expression Effect of SLC7A5/SLC3A2 to Predict Response to Endocrine Therapy in Oestrogen-Receptor-Positive Breast Cancer

Alfarsi, Lutfi H; El-Ansari, Rokaya; Craze, Madeleine L; Masisi, Brendah K; Mohammed, Omar J; Rakha, Emad A; Ellis, Ian O; Green, Andrew R.

Abstract

The majority of breast cancers are oestrogen receptor positive (ER+) and are subject to endocrine therapy however, an unpredictable subgroup of patients will develop resistance to endocrine therapy. SLC7A5/SLC3A2 complex is a major route for the transport of large neutral essential amino acids through the plasma membrane. Alterations in the expression and function of those amino acid transporters lead to metabolic reprogramming, which contributing to the tumorigenesis and drug resistance. This study aims to assess the effects and roles of SLC7A5/SLC3A2 co-expression in predicting response to endocrine therapy in patients with ER+ breast cancer. The biological and clinical impact of SLC7A5/SLC3A2 co-expression was assessed in large annotated cohorts of ER+/HER2- breast cancer with long-term follow-up at the mRNA and protein levels. In vitro experiments were conducted to investigate the effect of SLC7A5/SLC3A2 knockdown in the proliferation of cancer cells and to the sensitivity to tamoxifen. We found that proliferation-related genes are highly expressed in subgroup of patients with high SLC7A5/SLC3A2, and knockdown of SLC7A5/SLC3A2 decreased proliferation of ER+ breast cancer cells. In patients treated with endocrine therapy, high SLC7A5/SLC3A2 co-expression was associated with poor patient outcome, and depletion of SLC7A5/SLC3A2 using siRNA increased the sensitivity of breast cancer cells to tamoxifen. On the basis of our findings, SLC7A5/SLC3A2 co-expression has the potential of identifying a subgroup of ER+/HER2- breast cancer patients who fail to benefit from endocrine therapy and could guide the choice of other alternative therapy.

Citation

Alfarsi, L. H., El-Ansari, R., Craze, M. L., Masisi, B. K., Mohammed, O. J., Rakha, E. A., …Green, A. R. (2020). Co-Expression Effect of SLC7A5/SLC3A2 to Predict Response to Endocrine Therapy in Oestrogen-Receptor-Positive Breast Cancer. International Journal of Molecular Sciences, 21(4), Article 1407. https://doi.org/10.3390/ijms21041407

• Journal Article Type: Article
• Acceptance Date: Feb 17, 2020
• Online Publication Date: Feb 19, 2020
• Publication Date: Feb 2, 2020
• Deposit Date: Feb 17, 2020
• Publicly Available Date: Feb 20, 2020
• Journal: International Journal of Molecular Sciences
• Print ISSN: 1661-6596
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 21
• Issue: 4
• Article Number: 1407
• DOI: https://doi.org/10.3390/ijms21041407
• Keywords: Physical and Theoretical Chemistry; Inorganic Chemistry; Organic Chemistry; Spectroscopy; Molecular Biology; Catalysis; General Medicine; Computer Science Applications
• Public URL: https://nottingham-repository.worktribe.com/output/3978641
• Publisher URL: https://www.mdpi.com/1422-0067/21/4/1407