Erkan, Busra
(2025)
Prognostic significance of Glutamine-Related Solute Carriers in luminal breast cancer.
PhD thesis, University of Nottingham.
Abstract
Background
Breast cancer (BC) is a heterogeneous disease comprising diverse molecular and cellular subtypes. Oestrogen receptor-positive (ER+) BC accounts for approximately 75% of all BC cases. Although ER+ BC generally responds well to endocrine therapy, approximately 15% of tumours show intrinsic resistance, while an additional 30–40% develop resistance over time, leading to relapse, metastasis, and poor patient outcomes. Proliferating cancer cells heavily depend on glutamine for survival and growth. Glutamine is transported across the plasma membrane via Solute Carrier (SLC) proteins, where it serves as a key metabolic substrate to support energy production and biosynthesis of essential cellular components. This study aimed to provide a holistic view of SLCs expression in BC using multiple datasets. Among these SLCs, SLC1A5, SLC7A5, and SLC3A2 were associated with poor prognosis, particularly in highly proliferative ER+ BC/Lum B BC. Despite growing evidence highlighting the importance of these SLCs in metabolic regulation, their specific role in ER+ BC tumour progression remains unclear. Additionally, the individual and combined inhibition of these poor prognosis-associated SLCs was evaluated through functional assays to determine their impact on tumour progression in Lum BC cell lines. Furthermore, the study explored the therapeutic potential of novel genes associated with these SLCs, providing insights into their role in disease progression and potential as therapeutic targets.
Method
This study analysed the mRNA expression of fourteen SLCs in large BC patient cohorts: METABRIC (n=1,980), bc-GenExMiner (n=4,904), TCGA (n=1,211), and TIMER (n=1,100) for immune infiltration. Protein expression of HAO1 (n=1,793), CLIC6 (n=1,211), and TPRG1 (n=1,567) was investigated using immunohistochemical (IHC) analysis and tissue microarray (TMA) in a large, well-characterised primary BC cohort. Their expression was correlated with clinicopathological parameters, BC molecular subtypes, relevant biological markers, and patient outcomes. In a different approach, in vitro studies using MCF-7 and ZR-75-1 cell lines were carried out to investigate the effects of inhibition with the selective SLC1A5 and SLC7A5 inhibitors, V-9302 and KYT-0353, and siRNA knockdown of SLCs on cell viability, apoptosis, cell cycle, and glutamine assay.
Results
High mRNA expression of SLC1A5, SLC7A5, SLC3A2, SLC7A6, and SLC7A7 was associated with Lum B, HER2+, and basal-like subtypes in the PAM50 classification. SLC1A5 and SLC7A5 mRNA expression correlated with aggressive clinicopathological features, including higher tumour grade, larger tumour size, and higher lymph node involvement, and was significantly associated with shorter OS in ER+ BC. SLC1A5, SLC7A5, and SLC3A2 proteins showed both intra-tumoral and inter-tumoral heterogeneity in ER+/Lum BC tumours. The combined inhibition of SLC in Lum B BC cell lines had a greater impact on functional assays. Additionally, potential novel biomarkers associated with these SLCs were identified, including HAO1, CLIC6, and TPRG1, as prognostic and therapeutic targets.
Conclusion
Considering the heterogeneity of these SLCs in ER+ BC, a personalised approach to management is necessary to improve patient outcomes and develop classification strategies for clinical use. This thesis demonstrated that targeting glutamine-related SLCs synergistically may provide more potent therapeutic effects compared to targeting them individually. Further functional studies may increase insight into the roles of these SLCs in the Lum B subtype, contributing to improved patient outcomes.
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