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.

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.

Citation

Joseph, C., Alsaleem, M., Orah, N., Narasimha, P. L., Miligy, I. M., Kurozumi, S., Ellis, I. O., Mongan, N. P., Green, A. R., & 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

• Journal Article Type: Article
• Acceptance Date: May 2, 2020
• Online Publication Date: May 22, 2020
• Publication Date: 2020-07
• Deposit Date: May 7, 2020
• Publicly Available Date: May 23, 2021
• 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
• DOI: https://doi.org/10.1007/s10549-020-05670-x
• Keywords: MMP9; breast cancer; ECM remodelling; prognosis
• Public URL: https://nottingham-repository.worktribe.com/output/4388582
• Publisher URL: https://link.springer.com/article/10.1007%2Fs10549-020-05670-x