ATF4 as a Prognostic Marker and Modulator of Glutamine Metabolism in Oestrogen Receptor-Positive Breast Cancer
Pathobiology, cilt.91, sa.6, ss.411-421, 2024 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 91 Sayı: 6
- Basım Tarihi: 2024
- Doi Numarası: 10.1159/000539564
- Dergi Adı: Pathobiology
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
- Sayfa Sayıları: ss.411-421
- Anahtar Kelimeler: Activating-transcription factor 4, Amino acid transporters, Breast cancer, Glutamine metabolism
- İnönü Üniversitesi Adresli: Evet
Özet
Introduction: 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 = 1,980), GeneMiner (n = 4,712), and KM-Plotter datasets. Proteomic expression was assessed via immunohistochemistry (n = 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. Results: Genomic, transcriptomic, and proteomic overexpression of ATF4 was associated with more aggressive ERnegative 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 personalized treatment strategies.