High expression of STAT3 within the tumour-associated stroma predicts poor outcome in breast cancer patients

Pennel, K., Morrow, E., Hatthakarnkul, P. , Leslie, H. , Mallon, E., Andersen, D., Jamieson, N. , McMillan, D. , Roseweir, A. and Edwards, J. (2023) High expression of STAT3 within the tumour-associated stroma predicts poor outcome in breast cancer patients. Cancer Medicine, 12(12), pp. 13225-13240. (doi: 10.1002/cam4.6014) (PMID:37199043) (PMCID:PMC10315752)

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Introduction: Triple-negative breast cancer (TNBC) patients have the poorest clinical outcomes compared to other molecular subtypes of breast cancer. IL6/JAK/STAT3 signalling is upregulated in breast cancer; however, there is limited evidence for its role in TNBC. This study aimed to assess the expression of IL6/JAK/STAT3 in TNBC as a prognostic biomarker. Methods: Tissue microarrays consisting of breast cancer specimens from a retrospective cohort (n = 850) were stained for IL6R, JAK1, JAK2 and STAT3 via immunohistochemistry. Staining intensity was assessed by weighted histoscore and analysed for association with survival/clinical characteristics. In a subset of patients (n = 14) bulk transcriptional profiling was performed using TempO-Seq. Nanostring GeoMx® digital spatial profiling was utilised to establish the differential spatial gene expression in high STAT3 tumours. Results: In TNBC patients, high expression of stromal STAT3 was associated with reduced cancer-specific survival (HR = 2.202, 95% CI: 1.148–4.224, log rank p = 0.018). TNBC patients with high stromal STAT3 had reduced CD4+ T-cell infiltrates within the tumour (p = 0.001) and higher tumour budding (p = 0.003). Gene set enrichment analysis (GSEA) of bulk RNA sequencing showed high stromal STAT3 tumours were characterised by enrichment of IFNγ, upregulation of KRAS signalling and inflammatory signalling Hallmark pathways. GeoMx™ spatial profiling showed high stromal STAT3 samples. Pan cytokeratin (panCK)-negative regions were enriched for CD27 (p < 0.001), CD3 (p < 0.05) and CD8 (p < 0.001). In panCK-positive regions, high stromal STAT3 regions had higher expression of VEGFA (p < 0.05). Conclusion: High expression of IL6/JAK/STAT3 proteins was associated with poor prognosis and characterised by distinct underlying biology in TNBC.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Jamieson, Professor Nigel and Mallon, Dr Elizabeth and Roseweir, Dr Antonia and Pennel, Miss Kathryn and Leslie, Ms Holly and Edwards, Professor Joanne and Morrow, Dr Elizabeth and Hatthakarnkul, Phimmada and McMillan, Professor Donald
Authors: Pennel, K., Morrow, E., Hatthakarnkul, P., Leslie, H., Mallon, E., Andersen, D., Jamieson, N., McMillan, D., Roseweir, A., and Edwards, J.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Cancer Medicine
ISSN (Online):2045-7634
Published Online:18 May 2023
Copyright Holders:Copyright © 2023 The Authors
First Published:First published in Cancer Medicine 12(12): 13225-13240
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
313949National Productivity Investment Fund StudentshipsGeorge BaillieMedical Research Council (MRC)MR/R502327/1MVLS - Graduate School