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

• Published in: International journal of molecular sciences Vol. 21; no. 4; p. 1407
• Main Authors: Alfarsi, Lutfi H., El-Ansari, Rokaya, Craze, Madeleine L., Masisi, Brendah K., Mohammed, Omar J., Ellis, Ian O., Rakha, Emad A., Green, Andrew R.
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 19.02.2020
• Subjects: Antineoplastic Agents, Hormonal - therapeutic use; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Proliferation - genetics; Cohort Studies; Drug Resistance, Neoplasm - genetics; Female; Fusion Regulatory Protein 1, Heavy Chain - genetics; Fusion Regulatory Protein 1, Heavy Chain - metabolism; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Gene Knockdown Techniques; Humans; Kaplan-Meier Estimate; Large Neutral Amino Acid-Transporter 1 - genetics; Large Neutral Amino Acid-Transporter 1 - metabolism; Middle Aged; Neoplasm Metastasis - genetics; Prognosis; Receptors, Estrogen - metabolism; Regression Analysis; RNA, Small Interfering; Tamoxifen - pharmacology; Tamoxifen - therapeutic use; SLC7A5; breast cancer; SLC3A2; oestrogen receptor; endocrine resistance
• ISSN: 1422-0067; 1422-0067
• DOI: 10.3390/ijms21041407

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. The 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 contributes to the tumorigenesis and drug resistance. This study aims to assess the effects and roles of SLC7A5/SLC3A2 co-expression in predicting responses 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 a 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 therapies.