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

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

doi:10.1007/s10549-020-05670-x

Abstract

PurposeMMP9 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).MethodsMMP9 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.ResultsMMP9 immunopositivity was observed in the stroma and cytoplasm of BC cells. Elevated MMP9 protein levels were 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.ConclusionThis 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.

Highlights

Matrix metalloproteinases (MMPs) are a family of proteases that have multiple biological functions in cancer development and progression and are abundantly up regulated in breast cancer (BC)
MMP9 expression is regulated by several molecular pathways such as extracellular signal-regulated kinase (ERK), mitogenactivated protein kinase (MAPK), and phosphoinositide3-kinase–protein kinase (PI3K); pathways recognised to be altered in BC [7]
Full-face BC tissue (n = 10) sections were used to evaluate the pattern of MMP9 protein expression prior to staining of tissue microarrays (TMAs)

Summary

Introduction

Matrix metalloproteinases (MMPs) are a family of proteases that have multiple biological functions in cancer development and progression and are abundantly up regulated in breast cancer (BC). MMP9, known as gelatinase B, plays an important role in extracellular matrix (ECM) remodelling, protein cleavage, and is associated with tumour invasion, metastasis and modulation of tumour microenvironment [1, 2]. MMP9 is secreted as an inactive pro-enzyme and activation of latent MMP9 is the critical step in its regulation [4]. In vitro and in vivo experiments in human and experimental models of cancers reveal that the increased MMP9 expression is related to tumour progression [5, 6]. MMP9 expression is regulated by several molecular pathways such as extracellular signal-regulated kinase (ERK), mitogenactivated protein kinase (MAPK), and phosphoinositide3-kinase–protein kinase (PI3K); pathways recognised to be altered in BC [7]. The regulation of the MMPs, MMP9, by p53 has been documented [9]

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