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

Abstract

<b><i>Introduction:</i></b> 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. <b><i>Methods:</i></b> ATF4 expression was evaluated at genomic and transcriptomic levels using METABRIC (<i>n</i> = 1,980), GeneMiner (<i>n</i> = 4,712), and KM-Plotter datasets. Proteomic expression was assessed via immunohistochemistry (<i>n</i> = 2,225) 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 were investigated. <b><i>Results:</i></b> 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 (<i>p</i> &lt; 0.01) and SLC7A11 (<i>p</i> &lt; 0.02). High ATF4 and SLC1A5 protein expression was significantly associated with shorter breast cancer-specific survival (<i>p</i> &lt; 0.01), especially in ER+ tumours (<i>p</i> &lt; 0.01), while high ATF4 and SLC7A11 protein expression was associated with shorter survival (<i>p</i> &lt; 0.01). <b><i>Conclusion:</i></b> 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 personalized treatment strategies.