ATF4 as a Prognostic Marker and Modulator of Glutamine Metabolism in Estrogen Receptor Positive Breast Cancer

Patel, Roshni; Alfarsi, Lutfi H.; El-Ansari, Rokaya; Masisi, Brendah K.; Erkan, Busra; Fakroun, Ali; Ellis, Ian O.; Rakha, Emad A.; Green, Andrew R.

Abstract

Purpose: ATF4, a stress-responsive transcription factor that upregulates adaptive genes, is a potential prognostic marker and modulator of glutamine metabolism in breast cancer. However, its exact role remains to be elucidated.

Methods: ATF4 expression was evaluated at genomic and transcriptomic levels using METABRIC (n=1980), GeneMiner (n=4712) and KM-Plotter datasets. Proteomic expression was assessed via immunohistochemistry (n=2225) in the Nottingham Primary Breast Cancer Series. ATF4 genomic copy number (CN) variation and mRNA/protein in association with clinicopathological parameters, amino acid transporters (AATs), and patient outcome was investigated.

Results:
Genomic, transcriptomic, and proteomic overexpression of ATF4 was associated with more aggressive ER-negative tumours. ATF4 mRNA and protein expression were significantly associated with increased expression of glutamine related AATs including SLC1A5 (p<0.01) and SLC7A11 (p<0.02). High ATF4 and SLC1A5 protein expression was significantly associated with shorter breast cancer-specific survival (p<0.01), especially in ER+ tumours (p<0.01), while high ATF4 and SLC7A11 protein expression was associated with shorter survival (p<0.01).

Conclusion: These findings suggest a complex interplay between ATF4 and AATs in breast cancer biology and underscore the potential role for ATF4 as a prognostic marker in ER+ breast cancer, offering a unique opportunity for risk stratification and personalised treatment strategies.

Citation

Patel, R., Alfarsi, L. H., El-Ansari, R., Masisi, B. K., Erkan, B., Fakroun, A., Ellis, I. O., Rakha, E. A., & Green, A. R. (2024). ATF4 as a Prognostic Marker and Modulator of Glutamine Metabolism in Estrogen Receptor Positive Breast Cancer. Pathobiology, 91(6), 411-421. https://doi.org/10.1159/000539564

• Journal Article Type: Article
• Acceptance Date: May 25, 2024
• Online Publication Date: Jun 11, 2024
• Publication Date: 2024-12
• Deposit Date: May 28, 2024
• Publicly Available Date: Jun 11, 2024
• Journal: Pathobiology
• Print ISSN: 1015-2008
• Electronic ISSN: 1423-0291
• Publisher: Karger Publishers
• Peer Reviewed: Peer Reviewed
• Volume: 91
• Issue: 6
• Pages: 411-421
• DOI: https://doi.org/10.1159/000539564
• Keywords: activating-transcription factor 4; breast cancer; glutamine metabolism; amino-acid transporters 2
• Public URL: https://nottingham-repository.worktribe.com/output/35429989
• Publisher URL: https://karger.com/pat/article/doi/10.1159/000539564/909095/ATF4-as-a-Prognostic-Marker-and-Modulator-of