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

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=1341) in the Nottingham Primary Breast Carcinoma 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.