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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.

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


Authors

Roshni Patel

Lutfi H. Alfarsi

Rokaya El-Ansari

Brendah K. Masisi

Busra Erkan

Ali Fakroun

Ian O. Ellis

EMAD RAKHA Emad.Rakha@nottingham.ac.uk
Professor of Breast Cancer Pathology



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., …Green, A. R. (in press). ATF4 as a Prognostic Marker and Modulator of Glutamine Metabolism in Estrogen Receptor Positive Breast Cancer. Pathobiology, https://doi.org/10.1159/000539564

Journal Article Type Article
Acceptance Date May 25, 2024
Online Publication Date Jun 11, 2024
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
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

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