Breast cancer (BC) is one of the most common
malignancies among women globally, with ~2.1 million newly
diagnosed cases of BC in 2018 and 626,679 mortalities worldwide
(1). On account of improvements in
treatment and early detection by mammography, the 5-year overall
survival (OS) rate has notably improved by 12% and the mortality
rate has declined by 40% over the past three decades (2). However, due to the multi-aspect
dysregulation of genes and the complicated mechanisms that involve
several molecular and pathological subtypes, the efficiency of
accurate target therapies for patients with BC remains unclear
(3). The examination of BC
pathogenesis and identifying novel targets for the treatment of BC
is required for the development of medical science. Therefore, in
order to reach the goal of individualized treatment, it is crucial
and urgent to identify novel biological markers in the
microenvironment in BC.
In invasive and metastatic tumors, the
zinc-dependent matrix metalloproteases (MMPs) are the most
plentiful class of non-serine proteases present, first identified
in 1962 by Gross and Lapiere (4).
They have the ability to degrade the components of the
extracellular matrix (5). At
present, >20 MMPs have been identified in humans (6), including collagenases, gelatinases,
stromelysins, and the transmembrane type MMPs (7). MMPs can regulate a number of changes in
the microenvironment during tumor progression (such as in signaling
pathways that control cell growth, inflammation or angiogenesis,
and may also function in a non-proteolytic manner) (8). Their enzymatic activity modulates the
activities of a wide range of extracellular and intracellular
proteins, including proliferation, migration, and adhesion
(9). A previous study (10) showed that enhanced expression of MMPs
is usually associated with BC invasion and metastasis, and acts as
an important prognostic indicator. Therefore, an in-depth
bioinformatics analysis associated with MMPs and patients with BC
is required. In order to clarify the prognostic and potential
therapeutic value of MMPs in BC treatment, this study analyzed the
clinicopathological and survival data associated with MMPs in
patients with BC, based on a number of large public databases.
A total of 23 MMPs were identified using the
ONCOMINE database. The expression level of MMPs was analyzed in 20
types of cancer, and compared with that in normal individuals.
Fig. 1 shows the transcription
levels of MMPs in various types of cancers. High expression was
defined when MMPs expression was higher than that of adjacent
non-tumors, and vice versa. The mRNA expression of
MMP1/3/9/10/11/12/13 was upregulated in BC specimens in different
studies (Fig. 1). According to the
TCGA breast dataset, MMP1 was indicated to be highly expressed in
several types of BC compared with normal tissues and the
fold-change was 11.611 in invasive BC (Table SI). Richardson et al
(15) reported that the fold-change
of MMP1 in ductal BC was 21.13, whereas studies by Sorlie et
al (16,17) demonstrated fold changes of 2.963 and
2.482 for MMP1 in ductal BC. Compared with normal tissues, MMP3 was
overexpressed in some types of BC. The fold-change of invasive
lobular BC in TCGA data was 5.945, while Curtis et al
(18) reported that the fold-change
of MMP3 in invasive lobular BC was 2.008. According to the TCGA
dataset, MMP9 was overexpressed in almost all types of BC and
normal breast tissues, including intraductal cribriform BC with
fold-change=5.463, mucinous BC with fold-change=4.783 and invasive
BC with fold-change=3.245. Curtis et al (18) reported that the fold-changes of MMP9
in medullary BC and ductal BC in situ were 9.238 and 6.629,
respectively. In different datasets for MMP9, a fold-change of
4.378 in invasive ductal BC compared with normal breast was
observed (18). Radvanyi et
al (19) (fold-change=4.043) and
Turashvili et al (20)
(fold-change=3.640) found similar trends.
According to TCGA dataset, the transcriptional
levels of MMP10 showed fold-changes of 6.767, 4.265, and 4.130, in
invasive BC, invasive ductal BC and invasive lobular BC,
respectively. On the other hand, Turashvili et al (20) reported invasive ductal BC with an
MMP10 fold-change of 2.596. Radvanyi et al (19) and Karnoub et al (21) reported that MMP11 expression
increased significantly in ductal BC in situ and invasive
ductal BC stroma, with a fold-change of 2.639 and 188.233
respectively. Compared with normal breast tissue, upregulated
expression of MMP12 and MMP13 were also found in most types of BC
(Table SI).
Based on the median expression value of each MMP in
all samples, all types of patients with BC were divided into two
groups to detect MMP expression (high expression vs. low
expression). The Kaplan-Meier curves of survival data showed that
increased expression of MMP 2/10/16/19/20/23B/27 and reduced
expression of MMP 1/8/9/11/12 were associated with better RFS rate
(P<0.05) in all BC types (Fig.
2). In addition, patients with BC with lower MMP1/3/11/12/13
transcriptional expression levels indicated better DMFS rate
(Fig. 3A), and lower mRNA levels of
MMP1/12 exhibited better OS rate than those with high expression
(Fig. 3B). To further examine the
role of MMPs in BC prognosis, the Bc-GenExMiner version 4.1 was
used to validate this research. MMP1/9/11/12/13/14/15 has a
significant negative impact on the prognosis of patients. High
expression of MMP16/20 was associated with better prognosis
(Table I).
Using the aforementioned databases, this study
subsequently focused on whether MMP1/9/11/12/13 and MMP16/20 play a
key role in the progression of BC (Fig.
4A). Scarff, Bloom and Richardson grade (SBR) is one of the
important pathological parameters to be evaluated for the
management of breast carcinoma (22,23). The
survival rate of patients with poorly differentiated cancer (grades
II and III) was lower than that of patients with
well-differentiated cancer (grade I) (23). Using the Bc-GenExMiner software, it
was observed that patients with high-grade tumors (grades II and
III) appeared to exhibit high levels of MMP 1/9/11/12 and low
levels of MMP 16/20 (Fig. 4B). In
addition to molecular subtypes, the Nottingham prognostic index
(NPI) is also a helpful prognostic model for patients with BC
(24). In Fig. 4C, it was indicated that MMP1/9/12/16
were associated with NPI: Patients with high-grade tumors expressed
high levels of MMP1/9/12 and lower levels of MMP16, which was
consistent with our previous data mentioned above.
Combined with this information, multiple
bioinformatics analyses identified MMP1/9/12/16 as potential
therapeutic targets for patients with BC. In order to visualize the
potential genes co-expressed with MMP1/9/12/16, the gene network
was constructed as shown in Fig. 6.
The network was designed to recognize potential interactions
between MMP1/9/12/16 and a number of other key proteins. The
network analysis can provide a series of gene candidates to help
clarify the molecular mechanism of MMPs involvement in BC.
MMPs have been identified as an important family of
proteinases associated with tumorigenesis and as key mediators of
tumor progression (27). MMPs can
mediate various events in the microenvironment during the
progression of tumors, such as inflammation, angiogenesis,
proliferation, migration, and adhesion (27). Due to their role in cancer, MMPs have
been speculated to serve as an effective therapeutic target
(28). However, in clinical trials,
marimastat, a broad-spectrum MMPs inhibitor, failed to prolong
progression-free survival of patients with metastatic BC (28). Despite the recent research
illustrating the complex role of MMPs, the role of different MMPs
in the progression and metastasis of BC remains elusive (29). To the best of our knowledge, this
research is the first comprehensive bioinformatics study to
elucidate specific MMPs, and their prognostic value and biological
function in breast cancer.
A previous study demonstrated that MMP1 mRNA
expression in BC tissues is higher than in normal breast tissue
(30). In addition, previously
published data reported that patients with BC and high MMP1
expression are associated with poor prognoses, such as shorter
relapse-free-survival (31), which
is consistent with our findings. In contrast, Kulic et al
(32) reported that patients with
lower expression levels of MMP1 had significantly shorter 5-year
survival rates than those with higher levels of MMP1, suggesting a
poor prognostic role of low levels of serum MMP1. An animal
experiment verified that MMP2 plays a role in the development of BC
metastases, regulated by astrocyte factors and the ERK1/2 signaling
pathway (33). Results on whether
MMP2 is associated with worse prognosis in patients with BC have
been contradictory. High MMP2 expression was reported to be
indicative of relatively poor patient prognosis in BC (34), while a meta-analysis indicated that
worse OS rate was not linked to MMP2-positive patients (35).
As a direct downstream target of microRNA-519d, MMP3
acted as an executive molecule for the carcinogenic effect of
microRNA-519d in BC (36). A mouse
model revealed that peroxidases induced the transcription of the
MMP3 gene, in turn, MMP3 promoted tumor growth, invasion and
metastasis (37). MMP3 has been
reported to contribute to BC by participating in cancer invasion
and metastasis, especially in ER-/PR-tumors (38). Vizoso et al (39) found that the high expression of MMP7
was associated with shorter recurrence-free survival in patients
with BC. Kim et al (40)
reported that compared with luminal A and HER2-overexpressing
subtype, MMP7 expression was significantly higher in the basal-like
subtype. Furthermore, findings have identified MMP7 as a new
mechanism through which forkhead box C1 can regulate the aggressive
phenotype of basal-like breast cancer and the tendency of
metastasis of these cancers (41).
However, circulating MMP7 expression levels are poor predictors of
BC development (42); therefore, an
in-depth study analysis is required. MMP8 was initially thought to
be produced only by neutrophils, however it was subsequently found
to be expressed by a large variety of other cell types (43), including breast cancer cells
(44). It has been reported that
MMP8 has a suppressive effect on tumor progression and metastasis,
particularly in protecting against lymph node metastasis, while the
molecular mechanisms underlying these effects are unclear (45).
MMP9 has been reported to be mainly expressed in the
positive region of proliferating cell nuclear antigen, and mediates
different signaling pathways to promote or inhibit BC progression
or metastasis (46). Wang et
al (47) reported that
activation of MMP9 by Kruppel like factor 8 serves as a new signal
transduction mechanism for invasion and metastasis of human BC. In
another study, recombinant WNT-5A was demonstrated to activate CD42
in BC cells, whereas WNT-5A signaling and constitutively active
Cdc42 both decreased MMP9 activity, thereby inhibiting the
migration and metastasis of BC cells (48). MMP10 was first cloned from the human
adenocarcinoma cDNA library (49).
Previously, senescent cells were determined to secrete increased
levels of MMPs, whereas MMP10 is uniformly upregulated in
fibroblasts undergoing senescence (50). MMP11 is expressed in the stromal
fibroblasts associated with epithelial cancer cells, and the high
level of MMP11 has been linked to the progression of cancer and the
adverse prognosis of BC (51).
MMP11, a proliferation-related gene, is reported to be
significantly associated with DMFS rate in HR−/
HER2+ BC (52). A number
of previous studies have shown that MMP11 functioned in BC via
insulin-like growth factor-1 signaling or as a downstream target of
oncogene or tumor suppressor microRNA (53,54).
Several studies have reported that MMP12 has a dual
role in cancer, including anti-angiogenesis (55), or tumor invasion and metastasis
(56). An animal experiment showed
that overexpressed MMP12 converts plasminogen to angiostatin by
cleaving the plasminogen precursor molecule, which then inhibits
angiogenesis (55). Another study
has identified MMP12 as a potential mediator for CXCR4 to increase
invasion (57). A number of studies
have reported that MMP13 is highly overexpressed in BC tissue,
which is a potential tumor marker for BC diagnosis and serves as a
therapeutic target for bone metastasis of BC (58,59).
Membrane type I-MMP14 is known to be involved in the initiation and
progression of angiogenesis through multiple mechanisms (60,61). The
MMP14 inhibitor has been reported to impede angiogenesis, and delay
tumor progression and the formation of metastatic lesions;
therefore, a selective MMP14 inhibitor may be a potential
therapeutic strategy for the treatment of BC (62). To the best of our knowledge, there
are a limited number of studies reporting on the relevance between
MMP16 and BC.
In this study, MMP1/9/12 mRNA levels were indicated
to be significantly overexpressed in BC and increased in higher SBR
grades, which suggested a rapid growth of metastatic tumors. This
result is in line with the aforementioned studies. In addition,
high levels of MMP 1/9/12 indicated that RFS rate in all patients
with BC is relatively short; thus, these MMPs may be considered as
potential therapeutic targets. In the present study, the
transcriptional expression and prognostic value of all MMPs in BC
was systematically analyzed, providing a deeper understanding of
the complex mechanisms in the molecular biology of BC. Integrative
bioinformatics analysis showed that MMP1/9/12/16 could be potential
targets for the precise treatment of BC compared with other MMPs;
however, the lack of clinical samples is a limitation of the
present study. Additional clinical trials are required to validate
the diagnostic potentials of these MMPs. In addition, more in-depth
experiments, such as single-cell sequencing, are essential to
examine the latent interaction mechanism between cancer cells and
stromal cells in BC.
Not applicable.
No funding was received.
The datasets used and analyzed during the present
study are available from the corresponding author on reasonable
request.
YZ carried out the design of this study. YZ and HX
performed the statistical analysis and drafted the manuscript. WY
and ML made substantial contributions to acquisition of data and
helped to revise the manuscript. HL, WP and LW participated in its
design and coordination and also helped to draft the manuscript.
All authors read and approved the final manuscript.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
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