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

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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 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.

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.

Electronic supplementary material

The online version of this article (10.1007/s10549-020-05670-x) contains supplementary material, which is available to authorized users.

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Most cited references 44

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Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.

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The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.

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REporting recommendations for tumour MARKer prognostic studies (REMARK)

L M McShane, D Altman, W Sauerbrei … (2005)

Despite years of research and hundreds of reports on tumour markers in oncology, the number of markers that have emerged as clinically useful is pitifully small. Often initially reported studies of a marker show great promise, but subsequent studies on the same or related markers yield inconsistent conclusions or stand in direct contradiction to the promising results. It is imperative that we attempt to understand the reasons that multiple studies of the same marker lead to differing conclusions. A variety of methodological problems have been cited to explain these discrepancies. Unfortunately, many tumour marker studies have not been reported in a rigorous fashion, and published articles often lack sufficient information to allow adequate assessment of the quality of the study or the generalisability of the study results. The development of guidelines for the reporting of tumour marker studies was a major recommendation of the US National Cancer Institute and the European Organisation for Research and Treatment of Cancer (NCI-EORTC) First International Meeting on Cancer Diagnostics in 2000. Similar to the successful CONSORT initiative for randomised trials and the STARD statement for diagnostic studies, we suggest guidelines to provide relevant information about the study design, preplanned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods. In addition, the guidelines suggest helpful presentations of data and important elements to include in discussions. The goal of these guidelines is to encourage transparent and complete reporting so that the relevant information will be available to others to help them to judge the usefulness of the data and understand the context in which the conclusions apply.

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Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting.

Chrisostomi Gialeli, Achilleas Theocharis, Nikos K Karamanos (2011)

Matrix metalloproteinases (MMPs) consist of a multigene family of zinc-dependent extracellular matrix (ECM) remodeling endopeptidases implicated in pathological processes, such as carcinogenesis. In this regard, their activity plays a pivotal role in tumor growth and the multistep processes of invasion and metastasis, including proteolytic degradation of ECM, alteration of the cell-cell and cell-ECM interactions, migration and angiogenesis. The underlying premise of the current minireview is that MMPs are able to proteolytically process substrates in the extracellular milieu and, in so doing, promote tumor progression. However, certain members of the MMP family exert contradicting roles at different stages during cancer progression, depending among other factors on the tumor stage, tumor site, enzyme localization and substrate profile. MMPs are therefore amenable to therapeutic intervention by synthetic and natural inhibitors, providing perspectives for future studies. Multiple therapeutic agents, called matrix metalloproteinase inhibitors (MMPIs) have been developed to target MMPs, attempting to control their enzymatic activity. Even though clinical trials with these compounds do not show the expected results in most cases, the field of MMPIs is ongoing. This minireview critically evaluates the role of MMPs in relation to cancer progression, and highlights the challenges, as well as future prospects, for the design, development and efficacy of MMPIs. © 2010 The Authors Journal compilation © 2010 FEBS.

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Author and article information

Contributors

Emad A. Rakha: Emad.Rakha@nottingham.ac.uk

Journal

Journal ID (nlm-ta): Breast Cancer Res Treat

Journal ID (iso-abbrev): Breast Cancer Res. Treat

Title: Breast Cancer Research and Treatment

Publisher: Springer US (New York )

ISSN (Print): 0167-6806

ISSN (Electronic): 1573-7217

Publication date (Electronic): 22 May 2020

Publication date PMC-release: 22 May 2020

Publication date (Print): 2020

Volume: 182

Issue: 2

Pages: 267-282

Affiliations

[1 ]GRID grid.4563.4, ISNI 0000 0004 1936 8868, Nottingham Breast Cancer Research Centre, School of Medicine, , University of Nottingham, ; Nottingham, UK

[2 ]GRID grid.412602.3, ISNI 0000 0000 9421 8094, Faculty of Applied Medical Sciences, Onizah Community College, , Qassim University, ; Qassim, Saudi Arabia

[3 ]GRID grid.411775.1, ISNI 0000 0004 0621 4712, Histopathology Department, Faculty of Medicine, , Menoufia University, ; Shibin El Kom, Egypt

[4 ]GRID grid.5386.8, ISNI 000000041936877X, Department of Pharmacology, , Weill Cornell Medicine, ; New York, 10065 USA

[5 ]GRID grid.4563.4, ISNI 0000 0004 1936 8868, Faculty of Medicine and Health Sciences, , University of Nottingham, ; Nottingham, LE12 5RD UK

[6 ]GRID grid.412920.c, ISNI 0000 0000 9962 2336, Division of Cancer and Stem Cells, Department of Histopathology, School of Medicine, , The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, ; Nottingham, NG5 1PB UK

Author information

Chitra Joseph http://orcid.org/0000-0003-2631-9266

Article

Publisher ID: 5670

DOI: 10.1007/s10549-020-05670-x

PMC ID: 7297818

PubMed ID: 32445177

SO-VID: 6245468b-8dc3-492c-bf68-1c648dee7ac5

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 26 November 2019

Date accepted : 5 May 2020

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: mmp9,breast cancer,ecm remodelling,prognosis

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: mmp9, breast cancer, ecm remodelling, prognosis

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

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Abstract

Purpose

Methods

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Electronic supplementary material

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Karger: Oncology

Most cited references 44

Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.

REporting recommendations for tumour MARKer prognostic studies (REMARK)

Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting.

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Cited by 31

Most referenced authors 1,494