Landscape Analysis of Matrix Metalloproteinases Unveils Key Prognostic Markers for Patients With Breast Cancer.

Tianyi Cheng,Jingyi Chen,Yingtong Deng,Chen Huang,Peiying Chen

doi:10.3389/fgene.2021.809600

Tianyi Cheng, Jingyi Chen + Show 3 more

Open Access

https://doi.org/10.3389/fgene.2021.809600

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Abstract

Breast cancer (BRCA) is the most common cancer in the world, of which incidence rate and mortality are the highest in women. Being responsible for the remodeling and degradation of extracellular matrix proteins, matrix metalloproteinases (MMPs) have been regarded as one of the most important protease family related to tumorigenesis. It has been demonstrated that MMPs play crucial roles in some tumor invasion and metastasis. However, the potential roles of MMPs in tumorigenesis and progression of BRCA and its subtype remain elusive. Herein, we conducted a systematic study on MMPs via a series of database-based retrospective analysis, including TCGA, R Studio, GEPIA, Kaplan-Meier Plotter, cBioPortal, STRING, GeneMANIA and TIMER. As a result, many MMP family members were differentially expressed in patients with BRCA, e.g., the expressions of MMP1, MMP9, MMP11 and MMP13 were up-regulated, whereas the expression levels of MMP19 and MMP28 were down-regulated. MMP9, MMP12, MMP15 and MMP27 were significantly correlated with the clinical stages of BRCA, implying their important roles in the occurrence and development of BRCA. In addition, the survival analysis indicated that different expression pattern of MMPs exhibited distinct outcomes in patient with BRCA, e.g., patients with high expression of MMP2, MMP8, MMP16, MMP17, MMP19, MMP20, MMP21, MMP24, MMP25, MMP26 and MMP27 had a prolonged survival time, while the others (MMP1, MMP7, MMP9, MMP12 and MMP15) exhibited poor prognosis. Subsequent functional and network analysis revealed MMPs were mainly correlated with parathyroid hormone synthesis and secretion pathway, collagen metabolism, and their effect on the activities of serine hydrolase, serine peptidase and aminopeptidase. Notably, our analysis showed that the expression of MMPs was significantly correlated with the infiltration of various immune cells in BRCA, including CD8+T cells, CD4+T cells, macrophages, neutrophils, B cells, and dendritic cells, suggesting the close correlations between MMPs and immune functions. In short, our study disclosed MMPs play multiple biological roles in the development of BRCA, MMP1 and MMP9 might be used as independent prognostic markers and potential therapeutic targets for diagnosis and treatment for patients with BRCA.

Highlights

1.1 BackgroundIn 2020, breast cancer (BRCA) has become the most common cancer worldwide, replacing lung cancer (Sung et al, 2021)
Through the GEPIA database, we compared the mRNA expression of Matrix metalloproteinases (MMPs) in tumor with normal breast tissues, including 1085 BRCA samples and 291 normal tissue samples
The results showed that the expression levels of MMP1, MMP9, MMP11, and MMP13 were significantly up-regulated (p < 0.05) in BRCA (Figure 1A) The expression levels of MMP19 and MMP28, in BRCA were significantly decreased compared with normal samples (p < 0.05) (Figure 1A)

Summary

Introduction

1.1 BackgroundIn 2020, breast cancer (BRCA) has become the most common cancer worldwide, replacing lung cancer (Sung et al, 2021). BRCA diagnostic examinations such as mammography, computed tomography, magnetic resonance imaging, biopsy, ultrasound, and molecular imaging had made a significant progression, mortality is still progressively increasing because BRCA is undetected in initial stages and breast tumor can metastasize (Perez-Rivas et al, 2012). BRCA has no obvious characteristics, which is often ignored by patients and makes them blunder away the most appropriate treatment time (Ren et al, 2020). The limitation relates to the evidence that available tumor markers show low levels of sensitivity (Lawicki et al, 2016), which makes the necessity of potential constructive diagnostic methods of detection. Previous studies have shown that the major reason for the death of BRCA patients is the invasion and metastasis of breast tumors (Curigliano et al, 2017). Mechanisms and drugs that effectively inhibit tumor cell migration and invasion have become hotspots (Luo and Zhou 2020)

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