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Elevated MMP9 expression in breast cancer is a predictor of shorter patient survival

Joseph, Chitra; Alsaleem, Mansour; Orah, Nnamdi; Narasimha, Pavan L.; Miligy, Islam M.; Kurozumi, Sasagu; Ellis, Ian O.; Mongan, Nigel P.; Green, Andrew R.; Rakha, Emad A.

Authors

Mansour Alsaleem

Nnamdi Orah

Pavan L. Narasimha

Sasagu Kurozumi

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



Abstract

Purpose: MMP9 is a matricellular protein associated with extracellular matrix (ECM) remodelling, that promotes tumour progression, and modulates the activity of cell adhesion molecules and cytokines. This study aims to assess the prognostic value of MMP9 and its association with cytoskeletal modulators in early-stage invasive breast cancer (BC).

Methods: MMP9 expression was evaluated by immunohistochemistry using a well-characterised series of primary BC patients with long-term clinical follow-up. Association with clinicopathological factors, patient outcome and ECM remodelling BC-biomarkers were investigated. METABRIC dataset, BC-GenExMiner v4.0 and TCGA were used for the external validation of MMP9 expression. GSEA gene enrichment analyses were used to evaluate MMP9 associated pathways.

Results: MMP9 immunopositivity was observed in the stroma and cytoplasm of BC cells. Elevated MMP9 protein levels was associated with high tumour grade, high Nottingham Prognostic Index, and hormonal receptor negativity. Elevated MMP9 protein expression correlated significantly with cytokeratin 17 (Ck17), Epidermal Growth Factor Receptor (EGFR), proliferation (Ki67) biomarkers, cell surface adhesion receptor (CD44) and cell division control protein 42 (CDC42). Cytoplasmic MMP9 expression was an independent prognostic factor associated with shorter BC-specific survival. In the external validation cohorts, MMP9 expression was also associated with poor patients’ outcome. Transcriptomic analysis confirmed a positive association between MMP9 and ECM remodelling biomarkers. GSEA analysis supports MMP9 association with ECM and cytoskeletal pathways.

Conclusion: This study provides evidence for the prognostic value of MMP9 in BC. Further functional studies to decipher the role of MMP9 and its association with cytoskeletal modulators in BC progression are warranted.

Journal Article Type Article
Publication Date 2020-07
Journal Breast Cancer Research and Treatment
Print ISSN 0167-6806
Electronic ISSN 1573-7217
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 182
Pages 267–282
APA6 Citation Joseph, C., Alsaleem, M., Orah, N., Narasimha, P. L., Miligy, I. M., Kurozumi, S., …Rakha, E. A. (2020). Elevated MMP9 expression in breast cancer is a predictor of shorter patient survival. Breast Cancer Research and Treatment, 182, 267–282. https://doi.org/10.1007/s10549-020-05670-x
DOI https://doi.org/10.1007/s10549-020-05670-x
Keywords MMP9; breast cancer; ECM remodelling; prognosis
Publisher URL https://link.springer.com/article/10.1007%2Fs10549-020-05670-x

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