Tripartite Motif Containing 2, a glutamine metabolism-associated protein, predicts poor patient outcome in triple negative breast cancer treated with chemotherapy

Masisi, Brendah K.; El Ansari, Rokaya; Alfarsi, Lutfi; Fakroun, Ali; Erkan, Busra; Ibrahim, Asmaa; Toss, Michael; Ellis, Ian O.; Rakha, Emad A.; Green, Andrew R.

Abstract

Background: Breast cancer (BC) remains heterogeneous in terms of prognosis and response to treatment. Metabolic reprogramming is a critical part of oncogenesis and a potential therapeutic target. Glutaminase (GLS), which generates glutamate from glutamine, plays a role in triple-negative breast cancer (TNBC). However, targeting GLS directly may be difficult, as it is essential for normal cell function. This study aimed to determine potential targets in BC associated with glutamine metabolism and evaluate their prognostic value in BC. Methods: The iNET model was used to identify genes in BC that are associated with GLS using RNA-sequencing data. The prognostic significance of tripartite motif-containing 2 (TRIM2) mRNA was assessed in BC transcriptomic data (n = 16,575), and TRIM2 protein expression was evaluated using immunohistochemistry (n = 749) in patients with early-stage invasive breast cancer with long-term follow-up. The associations between TRIM2 expression and clinicopathological features and patient outcomes were evaluated. Results: Pathway analysis identified TRIM2 expression as an important gene co-expressed with high GLS expression in BC. High TRIM2 mRNA and TRIM2 protein expression were associated with TNBC (p < 0.01). TRIM2 was a predictor of poor distant metastasis-free survival (DMFS) in TNBC (p < 0.01), and this was independent of established prognostic factors (p < 0.05), particularly in those who received chemotherapy (p < 0.05). In addition, TRIM2 was a predictor of shorter DMFS in TNBC treated with chemotherapy (p < 0.01). Conclusions: This study provides evidence of an association between TRIM2 and poor patient outcomes in TNBC, especially those treated with chemotherapy. The molecular mechanisms and functional behaviour of TRIM2 and the functional link with GLS in BC warrant further exploration using in vitro models.

Citation

Masisi, B. K., El Ansari, R., Alfarsi, L., Fakroun, A., Erkan, B., Ibrahim, A., Toss, M., Ellis, I. O., Rakha, E. A., & Green, A. R. (2024). Tripartite Motif Containing 2, a glutamine metabolism-associated protein, predicts poor patient outcome in triple negative breast cancer treated with chemotherapy. Cancers, 16(11), Article 1949. https://doi.org/10.3390/cancers16111949

• Journal Article Type: Article
• Acceptance Date: May 17, 2024
• Online Publication Date: May 21, 2024
• Publication Date: Jun 1, 2024
• Deposit Date: May 15, 2024
• Publicly Available Date: May 21, 2024
• Journal: Cancers
• Electronic ISSN: 2072-6694
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 16
• Issue: 11
• Article Number: 1949
• DOI: https://doi.org/10.3390/cancers16111949
• Keywords: Glutaminase (GLS); Tripartite Motif Containing 2 (TRIM2); Triple-negative breast cancer (TNBC); Prognostic significance, Patient outcome, Molecular mechanism II
• Public URL: https://nottingham-repository.worktribe.com/output/34860857