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

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. 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.

Integrated Analysis of Key Differentially Expressed Genes Identifies DBN1 as a Predictive Marker of Response to Endocrine Therapy in Luminal Breast Cancer

“…Additionally, the amino acid transporter SLC7A5 was also among the upregulated DEGs in the unresponsive cases identified in this study. In support of this finding, we have previously along with others reported that SLC7A5 high expression correlates with poor clinical outcome and poor response to endocrine therapy in patients with luminal breast cancer [9][10][11]. Altogether, the above findings indicate a good reliability of the analysis performed in identifying the DEGs that are associated with prognosis in luminal breast cancer and sensitivity to endocrine treatment.…”

Identification of co-expression network correlated with different periods of adipogenic and osteogenic differentiation of BMSCs by weighted gene co-expression network analysis (WGCNA)

“…Three hub genes, SLC7A5, MYLIP, and DLX5 were overlapped between module green and DEGs of Ad4h. SLC7A5 (also known as LAT1), a sodium-independent Neutral Amino Acid transporter, has been widely investigated in various cancer cells [ 35 ]. Recently, Beaumatin et al, demonstrated that SLC7A5 could affect cellular growth, metabolic homeostasis, and differentiation by activating mTORC1 through DRAM-1, which was a key regulator for controlling adipocyte signalling and differentiation [ 36 ].…”

Multi cell line analysis of lysosomal proteomes reveals unique features and novel lysosomal proteins

“…The Ca 2+ channels MCOLN1, TPCN1, and TPCN2, for example, were expressed at very similar levels in all cell lines, while the amino acid and oligopeptide transporting members of the solute carrier (SLC) family showed both similar and highly variable expression patterns. SLC3A2 and SLC7A5, which are known to heterodimerize (Alfarsi et al, 2020), exhibited the highest dynamic range of all proteins in this group with differences of up to 135-fold between the highest (HeLa) and lowest (NIH3T3) expressing cell line, respectively. On the other hand, the sodium dependent amino acid transporter SLC38A7, which was shown to be essential for the extracellular protein dependent growth of cancer cells (Verdon et al, 2017), was with a dynamic range of protein expression of ~2-fold most stable.…”