The amino acid transporter SLC7A5 confers a poor prognosis in the highly proliferative breast cancer subtypes and is a key therapeutic target in luminal B tumours

Abstract

BackgroundBreast cancer (BC) is a heterogeneous disease characterised by variant biology and patient outcome. The amino acid transporter, SLC7A5, plays a role in BC although its impact on patient outcome in different BC subtypes remains to be validated. This study aimed to determine whether the clinicopathological and prognostic value of SLC7A5 is different within the molecular classes of BC.MethodsSLC7A5 was assessed at the genomic level, using Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) data (n = 1980), and proteomic level, using immunohistochemical analysis and tissue microarray (TMA) (n = 2664; 1110 training and 1554 validation sets) in well-characterised primary BC cohorts. SLC7A5 expression correlated with clinicopathological and biological parameters, molecular subtypes and patient outcome.ResultsSLC7A5 mRNA and protein expression were strongly correlated with larger tumour size and higher grade. High expression was observed in triple negative (TN), human epidermal growth factor receptor 2 (HER2)+, and luminal B subtypes. SLC7A5 mRNA and protein expression was significantly associated with the expression of the key regulator of tumour cell metabolism, c-MYC, specifically in luminal B tumours only (p = 0.001). High expression of SLC7A5 mRNA and protein was associated with poor patient outcome (p < 0.001) but only in the highly proliferative oestrogen receptor (ER)+/ luminal B (p = 0.007) and HER2+ classes of BC (p = 0.03). In multivariate analysis, SLC7A5 protein was an independent risk factor for shorter breast-cancer-specific survival only in ER+ high-proliferation tumours (p = 0.02).ConclusionsSLC7A5 appears to play a role in the aggressive highly proliferative ER+ subtype driven by MYC and could act as a potential therapeutic target. Functional assessment is necessary to reveal the specific role played by this transporter in the ER+ highly proliferative subclass and HER2+ subclass of BC.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-0946-6) contains supplementary material, which is available to authorized users.

SLCs contribute to endocrine resistance in breast cancer: role of SLC7A5 (LAT1)

“…Finally, we show that LAT1 overexpression is consistently associated with poor relapse free survival in four independent clinical datasets from ER+ patients that received an endocrine therapy. This observation is consistent with other reports that LAT1 may be an indicator of poor prognosis 25,61 . Taken together with the mechanistic outcomes reported here, further study of LAT1 and its role in endocrine therapy resistance may lead to novel therapeutic alternatives to improve overall survival for patients.…”

Heterogeneity of tumour‐infiltrating lymphocytes in breast cancer and its prognostic significance

“…16,17 The data on HER2 were already available for this early-stage BC cohort, and details of staining and scoring were included in previous publications. [18][19][20][21] Survival data were previously retrieved and updated, including: (i) BC-specific survival (BCSS), defined as the time (in months) from the date of primary surgical treatment to the time of death from BC; and (ii) distant metastasis-free survival (DMFS), defined as the time from the surgery until the first distant metastasis. In this study, post-recurrence survival was defined as the time (in months) from the date of surgical removal of the recurrent tumour to the date of death from BC.…”

Hypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine-resistance in breast cancer

“…This is particularly interesting as the luminal B subtype (ER+ subtype) has aggressive clinical behavior, with prognosis similar to that of HER2-enriched and basal-like group and a lower sensitivity to endocrine treatment compared to luminal A ER+ breast cancer (59). Interestingly, recent studies showed that a high expression of different AA transporters, such as SLC3A2 or SLC7A5, is related to poor outcomes in luminal B ER+ breast cancer subtype (60, 61). These data suggest that this subtype might be particular vulnerable to glutamine depletion.…”