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Prognostic role of microRNAs in breast cancer: A systematic review

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Oncotarget. 2019; 10:7156-7178. https://doi.org/10.18632/oncotarget.27327

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Eleni Zografos, Flora Zagouri, Despoina Kalapanida, Roubini Zakopoulou, Anastasios Kyriazoglou, Kleoniki Apostolidou, Maria Gazouli and Meletios-Athanasios Dimopoulos

Abstract

Eleni Zografos1, Flora Zagouri2, Despoina Kalapanida2, Roubini Zakopoulou2, Anastasios Kyriazoglou2, Kleoniki Apostolidou2, Maria Gazouli1 and Meletios-Athanasios Dimopoulos2

1 Department of Basic Medical Sciences, Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

2 Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

Correspondence to:

Eleni Zografos,email: el_[email protected]

Keywords: breast cancer; microRNAs; prognosis; biomarkers

Received: August 07, 2019     Accepted: October 26, 2019     Published: December 24, 2019

ABSTRACT

MicroRNAs (miRNAs) have been found to play an important role in breast cancer, functioning either as potential oncogenes or tumor suppressor genes, but their role in the prognosis of patients remains unclear. The aim of the present review study is to highlight recent preclinical and clinical studies performed on both circulating and tissue-specific miRNAs and their potential role as prognostic markers in breast cancer. We systematically searched the PubMed database to explore the prognostic value of miRNAs in breast cancer. After performing the literature search and review, 117 eligible studies were identified. We found that 110 aberrantly expressed miRNAs have been associated with prognosis in breast cancer. In conclusion, the collective data presented in this review indicate that miRNAs could serve as novel prognostic tools in breast cancer, while the clinical application of these findings has yet to be verified.


Introduction

Breast carcinoma is the leading cause of cancer death in women worldwide [1]. According to the GLOBOCAN 2018 worldwide estimates of cancer incidence and mortality, in 2018, about 2,088,849 new cases were diagnosed and approximately 626,679 women were predicted to die from the disease [2]. These data support the need to develop more efficient strategies for preventive intervention, evaluation of therapy, and prediction of prognosis [3].

Undoubtedly, TNM staging is of great prognostic value; however, considering all the limitations of the currently available prognostic strategies, it is overall recognized that new affordable more accurate methods indicative of molecular characteristics of tumors are needed to achieve personalized treatment [4]. Still, it remains difficult to achieve these goals, because of the absence of refined (sensitive and specific) biomarkers for disease monitoring and for addressing breast cancer on an individual basis.

MicroRNAs are a small class of endogenous, evolutionarily conserved, single-stranded noncoding RNAs, with a length of approximately 19–24 nucleotides [5]. Interaction between miRNAs and mRNAs, within the 3′untranslated region of the target genes, leads to the degradation or inhibition of mRNA translation [6]. In the past few years, miRNAs have attracted considerable attention in the cancer research field, due to their regulatory actions in multiple levels [7, 8]. Depending on the target gene that they regulate, miRNAs can either serve as “tumor suppressor miRs” by repressing oncogenes or as “onco-miRs” by targeting tumor suppressor genes. However, a number of miRNAs play both tumor suppressor and onco-miR roles depending on the cellular context and tumor type [9].

Particularly in breast cancer, microRNAs (miRNAs or miRs) have been proposed as promising biomarkers because they can be readily detected in tumor biopsies (non-circulating miRNAs) and can also be identified in blood, plasma, serum, and saliva (circulating miRNAs) [10]. Furthermore, circulating miRNAs are bound to lipoproteins such as HDL, are associated with Argonaute 2 (Ago2) protein, or are packaged into exosome-like microparticles, micro-vesicles, and apoptotic bodies [11]. Therefore, they are protected from endogenous RNAase activity, and hence they are reliable.

Several lines of evidence have proven that in breast cancer, the expression levels of miRNAs are altered due to key mechanisms, such as epigenetic control, transcription factors, or the effect of mutated proteins [10]. According to previous publications [12], miRNAs are considered as tumor suppressive or protective when they are down-regulated in cancer compared to their normal counterpart, or else, they are termed oncogenic miRNAs or onco-miRs. In this context, miRNAs are increasingly recognized as promising biomarkers, given the fact that they are easy to isolate, and they maintain their structural stability under different conditions of sample processing and isolation. A prognostic biomarker should indicate a patient’s outcome, for example disease recurrence or disease progression, independent of the treatment regimen that was followed, and they are highly desirable for personalized or precise patient treatment [13].

The aim of the present review is to highlight recent preclinical and clinical studies performed on both circulating and tissue-specific miRNAs and therefore to identify their potential role as prognostic markers in breast cancer. We will particularly focus on the potential role of miRNAs in breast cancer prognosis, and on how miRNAs have the potential to answer actual clinical needs, such as identification of biomarkers for prognosis, in order to achieve the goal of individualized breast cancer treatment.

Results

The search strategy retrieved 192 articles. Of these articles, 42 were irrelevant, 11 were reviews, eight (8) were meta-analyses, six (6) were retracted articles, three (3) were not in English, three (3) were duplicates, two (2) were comments and 117 were eligible. The aforementioned steps concerning the selection of studies are illustrated in detail in Figure 1. Therefore, a total of 117 articles were eligible for this systematic review and the prognostic role of 110 miRNA molecules is described (Table 1). Furthermore, we retrieved five studies, in which authors have identified six distinct microRNA signatures with prognostic value in breast cancer (Table 2).

Flow diagram of the study selection process.

Figure 1: Flow diagram of the study selection process.

Table 1: List of prognostic microRNAs in breast cancer

Prognostic microRNABreast cancer typeDetection methodPrognostic valueRoleBiological sampleReferences
let-7BC not
classified
qRT-PCRpotential prognostic
biomarker as altered levels
of miR-let-7 are associated
with metastases risk
tumor
suppressor
serum[56]
let-7-3pTNBCNGS, qRT-
PCR
independent prognostic
factor for OS, DFS
onco-miRFFPE[57]
let-7bluminal subtypeqRT-PCR,
LNA-ISH,
TMAs
independent prognostic
factor for OS associated
with luminal tumors
tumor
suppressor
FFPE[58]
let-7c/miR-
99a/miR-125b
cluster
estrogen-
dependent
BC cell line
Nanostring,
qRT-PCR,
luciferase assay
potential prognostic factor
for OS in the luminal A
subtype
tumor
suppressor
cell lines[59]
miR-1ER-positive,
stage IV BC
PCR,
microarray,
ISH, IHC
independent worse
prognostic factor of DFS
and BC-specific survival
associated with stage,
lymph node metastasis,
distant metastasis,
histological grade, ER
status, PR status and Ki-67
onco-miRFFPE[60]
miR-7BC not
classified
qRT-PCRpotential prognostic factor
for OS, DFS predictive
of an adverse response to
tamoxifen therapy
onco-miRfresh frozen
tissue, cell lines
[61]
miR-9TNBC,
BC not
classified
qRT-PCRprognostic factor of DFS
and DMFS, OS
onco-miRFFPE, fresh
frozen tissue,
cell lines
[62, 63]
miR-10bBC not
classified,
TNBC
qRT-PCRindependent prognostic
factor for DFS associated
with distant metastasis,
occurrence in TNBC,
associated with genico-
obstetric history
onco-miRFFPE, fresh
frozen tissue,
cell lines
[17, 40, 41, 64]
miR-15aTNBCqRT-PCRprognostic factor for OS,
DFS
tumor
suppressor
fresh frozen
tissue
[65]
miR-16triple
possitive
BC
qRT-PCR,
Western blot,
luciferase
report assay,
MTS assay
potentially tumor
suppressive effect on
cancer progression of ER
positive breast cancers,
impairment of cell proliferation
tumor
suppressor
FFPE[45]
miR-19anewly
diagnosed
IBC stage
III, IBC
stage IV,
non-IBC
stage II-IV
and HER2+
BC
qRT-PCRpotential prognostic factor
for OS, DFS in patients
with metastatic HER2(+)
IBC.
tumor
suppressor
serum, cell
lines
[66]
miR-19bBC not
classified
qRT-PCRprognostic factor for OS
associated with distant
metastasis and TNM stage
onco-miRfresh frozen
tissue, cell lines
[67]
miR-20b-5pBC not
classified
microRNA
arrays
potential prognostic factor
for DFS, correlated with
the presence of breast
tumor interstitial fluid
onco-miRFFPE,
interstitial
breast tumor
fluids, serum
[68]
miR-21stage II/III
BC, HER2
positive, TNBC
qRT-PCR,
microarray,
luciferase
report assay
independent prognostic
factor of OS, DFS,
prognostic biomarker for
resistance to trastuzumab,
to predict lymph node
metastases occurrence
in TNBC, to predict
high grade in non TNBC
possible, prognostic factor
in daughter of patients,
associated with genico-
obstetric history
onco-miRFFPE, serum,
fresh frozen
tissue, cell lines
[16-27]
miR-22BC not
classified
qRT-PCR,
ISH, luciferase
report assay
potential prognostic factor
for OS, DFS, associated
with EMT/metastasis
bothFFPE, cell lines[69, 70]
miR-24-2*.BC cell
lines
qRT-PCRassociated with tumor
suppressive activity
through the suppression of
cellular survival
tumor
suppressor
cell lines, fresh
frozen mouse
tissue
[71]
mir-24-3pBC not
classified
(stage I-III)
Nanostring
technology
potential prognostic
biomarker of occult
metastasis
onco-miRplasma[72]
miR-27aBC not
classified
ISH, IHCindependent prognostic
factor for OS, DFS
onco-miRFFPE[73]
miR-27b-3pTNBCqRT-PCRindependent prognostic
factor for OS, DMF survival
onco-miRFFPE[74]
miR-29aBC not
classified
qRT-PCR,
microarray
asocciated with
poor response and
chemotherapy resistance
onco-miRFFPE, cell lines[75]
miR-29blobular
and ductal
subtypes
qRT-PCRprognostic factor for OS,
DFS
tumor
suppressor
fresh frozen
tissue
[76, 77]
miR-30aTNBCNGS,
qRT-PCR,
microarray, luciferase assay
independent prognostic
factor for OS, DFS
tumor
suppressor
FFPE, cell lines[57, 78]
miR-30a-3pTNBCqRT-PCRprognostic factor for OS,
RFS
tumor
suppressor
FFPE[57]
miR-30a-5pTNBCNGSprognostic factor for OS,
RFS
tumor
suppressor
FFPE[57]
miR-30c-5pTNBCqRT-PCRprognostic factor for
RFS
tumor
suppressor
FFPE[57]
miR-30e*ESR1-/
ERBB2-
tumors
microarray,
ISH
prognostic factor for DFStumor
suppressor
fresh frozen
tissue
[79]
miR-34aBC not
classified
TNBC
qRT-PCR,
TMAs
prognostic factor for OS,
associated with response
and chemotherapy
resistance
both FFPE, plasma,
cell lines
[75, 80, 81]
miR-34bTNBCqRT-PCRprognostic factor for OS,
DFS
onco-miRFFPE[82]
miR-34cTNBCqRT-PCRindependent risk factor
for OS
tumor
suppressor
Plasma[81]
miR-93-5pBC not
classified
microRNA
arrays
potential prognostic factor
for DFS, correlated with
the presence of breast
tumor interstitial fluid
onco-miRFFPE,
interstitial
breast tumor
fluids, serum
[68]
miR-95-3pTNBCqRT-PCRprognostic factor for OS,
RFS in patients treated
with anthracycline-based
chemotherapy
onco-miRFFPE[57]
miR-96BC cell
lines
qRT-PCRpotential prognostic factor
for OS associated with
EMT and regulation of
growth factors involved in
G1/S-phase transition
onco-miRcell lines[44]
miR-99aBC not
classified
qRT-PCRpotential prognostic factor
for OS, independent risk
factor for breast cancer
tumor
suppressor
serum[83]
miR-122BC not
classified
(stage II-III)
qRT-PCR,
NGS
potential prognostic
factor for disease relapse,
predictor of metastasis
onco-miRserum[84]
miR-124BC not
classified
qRT-PCRprognostic factor for
OS associated with
advanced TNM stage,
lymph node metastasis
and poorer pathological
differentiation, associated
with age at diagnosis (>50
years old)
tumor
suppressor
FFPE, fresh
frozen tissue
[85, 86]
miR-125a-5pBC not
classified
microarray,
qRT-PCR,
luciferase
assay, ISH,
IHC
potential prognostic factor
for OS, progression-free
survival (PRS)
tumor
suppressor
serum, cell
lines
[87]
miR-125bHER2
positive BC,
stage II/III
qRT-PCR, ISHprognostic factor for
OS, DFS, associated
with aromatase inhibitor
esistant breast cancers
onco-miRFFPE, serum,
cell lines
[26, 88, 89]
miR-126-5pBC not
classified
microRNA
arrays
potential prognostic factor
for DFS
onco-miRFFPE,
interstitial
breast tumor
fluids, serum
[68]
miR-127BC not
classified
qRT-PCRprognostic factor of OStumor
suppressor
fresh frozen
tissue, cell lines
[90]
miR-128-3pTNBCqRT-PCRprognostic factor for RFStumor
suppressor
FFPE[57]
miR-129-5pBC not
classified
qRT-PCR,
luciferase
report assay
potential prognostic factor
for OS, DFS, associated
with EMT
tumor
suppressor
FFPE, fresh
frozen tissue,
cell lines
[91]
miR-133aBC not
classified
qRT-PCR,
TMA, ISH,
Luciferase assay
potential prognostic factor
for DFS associated with
migration and invasion
tumor
suppressor
FFPE, fresh
frozen tissue,
cell lines
[92]
miR-140BC not
classified
qRT-PCR,
microarray
asocciated with
poor response and
chemotherapy resistance
onco-miRFFPE, cell lines[75]
miR-141BC not
classified
microRNA
arrays, qRT-
PCR
potential prognostic factor
for OS, PFS associated
with circulating tumor
cells status
onco-miRplasma[33, 34]
miR-143Triple
possitive
BC
qRT-PCR,
Western blot,
luciferase
report assay,
MTS assay
potentially tumor
suppressive effect on
cancer progression of ER
positive breast cancers,
impairment of cell
proliferation
tumor
suppressor
FFPE[45]
miR-144BC not
classified
microRNA
arrays, qRT-
PCR
potential prognostic factor
for OS, PFS
tumor
suppressor
plasma[34]
miR-145BC not
classified
qRT-PCRpotential prognostic factor
for DFS, OS (3-year
survival rate)
tumor
suppressor
fresh frozen
tissue
[93, 94]
miR-146aBRCA1-
deficient
TNBC
tumors
qRT-PCRpotential prognostic factor
for OS
tumor
suppressor
FFPE, cell lines[95]
miR-148aTNBCqRT-PCR,
microarray
potential prognostic factor
for OS associated with
metastasis
tumor
suppressor
Cell lines,
mouse models
[96]
miR-155TNBC,
BC not
classified
qRT-PCR,
microarray,
luciferase
report assay
prognostic factor of
DMFS, associated with
lymph node metastasis
bothFFPE, fresh
frozen tissue,
cell lines
[62, 97]
miR-182BC not
classified,
TNBC
qRT-PCRpotential prognostic factor
to predict lymph node
metastases occurrence in
TNBC, associated with
genico-obstetric history,
related with hormonal
receptors
onco-miRFFPE, serum[17, 98]
miR-183/182/96
cluster
BC not
classified
qRT-PCR, ISHpotential prognostic factor
for OS, DFS
onco-miRbreast tissues
not classified,
cell lines
[99]
miR-187BC not
classified
TMA, ISHindependent prognostic
factor FOR breast cancer–
specific survival (BCSS)
onco-miRFFPE, cell lines[100]
miR-193bBC not
classified
microRNA
arrays, qRT-
PCR
potential prognostic factor
for OS, PFS
onco-miRplasma[34]
miR-195-5pBC not
classified
microRNA
arrays
potential prognostic factor
for DFS
onco-miRFFPE,
interstitial
breast tumor
fluids, serum
[68]
miR-199a-5pTNBCNGSprognostic factor for OStumor
suppressor
FFPE[57]
miR-199b-5pBC not
classified
(-II stage)
qRT-PCR,
assays in vitro
potential prognostic factor
for OS associated with
TNM stage and lymph
node metastasis
tumor
suppressor
fresh frozen
tissue and cell
lines
[101]
miR-200aBC not
classified
microRNA
arrays, qRT-
PCR
potential prognostic factor
for OS, PFS, associated
with circulating tumor
cells status, potential
to detect the onset of
metastasis
onco-miRplasma[33, 34]
miR-200bBC not
classified
qRT-PCR,
microRNA
arrays,
ISH, TMA,
luciferase
report assay
potential prognostic factor
for OS (independent),
PFS associated with
advanced clinical
stage, metastasis, cell
proliferation, apoptosis,
cell cycle distribution and
circulating tumor cells
status, potential to detect
the onset of metastasis
bothFFPE, plasma,
cell lines
[33, 34, 46, 47]
miR-200cBC not
classified
qRT-PCR,
microRNA
arrays
prognostic factor of OS,
DFS, potential to detect
the onset of metastasis,
associated with circulating
tumor cells status
onco-miRfresh frozen
tissue, plasma
[33, 34, 102]
miR-200c/141
cluster
BC not
classified,
TNBC
qRT-PCR,
CAT reporter
assay, siRNA
transfection,
Western blot
poor prognostic factor
in TNBC, promoting
metastasis
onco-miRFFPE, cell
lines, xenograft
animal model
[103]
miR-203BC not
classified,
ER positive
BC
microRNA
arrays, qRT-
PCR, Western
blot, luciferase
report assay,
MTS assay
potential prognostic factor
for OS, PFS associated
with EMT and circulating
tumor cells status
bothFFPE, plasma,
cell lines
[33, 34, 44, 45]
miR-203-5pTNBCNGSprognostic factor for OSonco-miRFFPE[57]
miR-203aductal
in situ,
invasive
ductal and
lobular carcinoma
qRT-PCRpotential prognostic
marker associated with
increased stage in invasive
lobular carcinomas
tumor
suppressor
FFPE[104]
miR-204BC not
classified
qRT-PCRpotential prognostic factor
for OS, DFS, correlated
with chemotherapeutic
resistance
tumor
suppressor
FFPE[105]
miR-205BC not
classified
qRT-PCR,
LNA-ISH,
TMAs, IHC
potential prognostic
factor for OS associated
with tumours of ductal
morphology, for OS and
DFS in early breast cancer
tumor
suppressor
FFPE[21, 58]
miR-206BC not
classified
qRT-PCR,
luciferase
report assay
potential prognostic factor
for OS
bothfresh frozen
tissue, cell lines
[94, 106, 107,
miR-210early first
primary BC,
TNBC
qRT-PCR,
microarray
independent prognostic
factor for OS, DFS,
associated with poor
clinical outcome in ER-
positive, tamoxifen-treated
BC patients, involved
in cell proliferation,
migration and invasion,
Potential to detect the
onset of metastasis prior
to clinical diagnosis,
associated with circulating
tumor cells status
onco-miRFFPE, fresh
frozen tissue,
plasma, cell
lines (Breast
cancer and
tumor-educated
macrophages)
[33-39]
miR-210-3pBC cell
lines
qRT-PCRpotential prognostic factor
for OS associated with
EMT and regulation of
growth factors involved in
G1- to S-phase transition
onco-miRcell lines[44]
miR-215BC not
classified
microRNA
arrays, qRT-
PCR
potential prognostic factor
for OS, PFS, Potential
to detect the onset of
metastasis prior to clinical
diagnosis
tumor
suppressor
plasma[34]
miR-218BC not
classified
qRT-PCRprognostic factor for OS
associated with lymph
node metastases, higher
grades,
tumor
suppressor
fresh frozen
tissue
[108]
miR-221BC not
classified
qRT-PCRprognostic factor for DFS,
OS, RFS
onco-miRFFPE, fresh
frozen tissue,
cell lines
[41, 63, 109]
miR-221-3pTNBCqRT-PCRprognostic factor for DFStumour
suppressor
FFPE, cell lines[110]
miR-222BC not
classified
qRT-PCR,
TMA
potential prognostic
factor related to lymph
node metastasis, down-
regulation of the estrogen
receptor, EMT, tumor
progression, poor response
and chemotherapy
resistance
onco-miRFFPE, fresh
frozen tissue,
cell lines
[75, 109]
miR-222-3pBC not
classified
qRT-PCR,
microarray
independent prognostic
factor for DFS
postoperatively
onco-miRserum[111]
miR-301aBC not
classified,
TNBC
qRT-PCR,
microarray,
ISH
prognostic factor for DFS,
OS
onco-miRFFPE[112, 113]
miR-320aBC not
classified
chromogenic
ISH
potential prognostic factor
for OS for invasive breast
cancer
tumor
suppressor
FFPE[114]
miR-324-5pTNBCNGSprognostic factor for OSonco-miRFFPE[57]
miR-329BC not
classified
qRT-PCRindependent prognostic
factor for OS
tumor-
suppressor
serum, fresh
frozen tissue,
cell lines
[115]
miR-330-3pBC not
classified
qRT-PCRpotential prognostic factor
for OS
onco-miRfresh frozen
tissue
[116]
miR-339-5pBC not
classified
qRT-PCR,
TMA, ISH
independent prognostic
factor for OS, DFS
tumor
suppressor
FFPE, cell lines[117]
miR-361-5pBC not
classified, TNBC
TMAs, ISHprognostic factor for DFStumor
suppressor
FFPE[118]
miR-365BC not
classified
microRNA
arrays, qRT-
PCR
potential prognostic factor
for OS
miR-365,
onco-miR
plasma[34]
miR-370BC not
classified
qRT-PCR,
TMA
potential prognostic factor
for DFS
onco-miRFFPE[119]
miR-374aBC not
classified,
IDC stage II
qRT-PCR,
TMAs,
Luciferase
assay, MTT
assays, IHC
potential prognostic factor
for DFS, contributes
to tumorigenicity and
progression
onco-miRFFPE, fresh
frozen tissue,
cell lines,
xenograft
mouse models
[120, 121]
miR-375BC not
classified,
stage II-III
locally
advanced
and IBC
patients
qRT-PCR,
microRNA
arrays, NGS
potential prognostic factor
for OS, PFS associated
with circulating tumor
cells status, related to
hormonal receptors
bothserum, plasma[33, 34, 84, 98]
miR-409-3pBC not
classified
qRT-PCRindependent prognostic
factor for OS associated
with advanced TNM stage,
lymph node metastasis,
and poorer pathological
differentiation
tumor
suppressor
fresh frozen
tissue
[112]
miR-423BC not
classified
qRT-PCR,
microarray
asocciated with
poor response and
chemotherapy resistance
onco-miRFFPE, cell lines[75]
miR-429BC not
classified
microRNA
arrays, qRT-
PCR
potential prognostic factor
for OS, PFS
miR-429
onco-miR
plasma[34]
miR-451BC cell
lines
qRT-PCRpotential factor associated
with cell survival and
endocrine resistance
tumor
suppressor
cell lines[123]
miR-454BC not
classified
(stage I-III)
TMA, ISHpotential prognostic
factor for OS (especially
in TNBC) and DFS,
associated with response
to anthracycline
onco-miRFFPE[124]
miR-454-3pBC not
classified
microRNA
arrays
potential prognostic factor
for DFS
onco-miRFFPE,
interstitial
breast tumor
fluids, serum
[68]
miR-486-5pBC not
classified
microRNA
arrays, qRT-
PCR
potential prognostic factor
for OS, Potential to detect
the onset of metastasis
prior to clinical diagnosis
tumor
suppressor
plasma[34]
miR-493TNBCTMAs, ISHprognostic factor for DFStumour
suppressor
FFPE[125]
miR-494node-
negative BC
ISH8.5-fold risk of breast
cancer death (association
trend-not clinical
significance)
tumour
suppressor
fresh frozen
tissue
[126]
miR-497BC not
classified,
TNBC
qRT-PCR,
luciferase assay
potential prognostic factor
for OS
tumor
suppressor
fresh frozen
tissue,
cell lines,
orthotopic
mouse models
[127, 128]
miR-548c-5pTNBCqRT-PCR, ISHindependent prognostic
factor for OS, DFS
onco-miRFFPE[39]
miR-574BC not
classified
qRT-PCR,
microarray
asocciated with
poor response and
chemotherapy resistance
onco-miRFFPE, cell lines[75]
miR-574-3pBC not
classified
qRT-PCR,
NGS
potential prognostic factor
for OS, DFS
tumor
suppressor
FFPE[129]
miR-588BC not
classified
qRT-PCRprognostic factor of OStumour
suppressor
fresh frozen
tissue, cell lines
[130]
miR-590-3pBC cell
lines
qRT-PCR,
luciferase
report assay
associated with breast
cancer cells viability,
growth and apoptosis
tumor
suppressor
cell lines[131]
miR-597BC not
classified
qRT-PCRprognostic factor of OStumor
suppressor
fresh tissue[132]
miR-601BC not
classified
qRT-PCRprognostic factor for
DFS associated with
cell proliferation and
metastasis
tumor
suppressor
FFPE, cell lines[133]
miR-638BC not
classified,
BRCA1-
deficient
TNBC
tumors
qRT-PCRindependent prognostic
factor for OS associated
with lymph node
metastasis and TNM stage
tumor
suppressor
FFPE, fresh
frozen, cell
lines
[95, 134]
miR-644aBC cell
lines
qRT-PCR,
luciferase
report assay
associated with tumor
progression and distant
metastasis-free survival
tumor
suppressor
cell lines[135]
miR-660-5pBC not
classified
qRT-PCR,
NGS
potential prognostic factor
for OS, DFS
onco-miRFFPE[129]
miR-711BC not
classified
qRT-PCRindependent prognostic
factor for OS, DFS,
associated with breast
cancer cells’ proliferation,
colony formation, invasion
onco-miRFFPE, cell lines[136]
miR-744BC not
classified
qRT-PCR,
microarray
associated with
poor response and
chemotherapy resistance
onco-miRFFPE, cell lines[75]
miR-801BC not
classified
microRNA
arrays, qRT-
PCR
potential prognostic factor
for OS, PFS associated
with circulating tumor
cells status
onco-miRplasma[33, 34]
miR-874BC not
classified
qRT-PCRprognostic factor for OStumour
suppressor
fresh frozen
tissue, cell lines
[137]
miR-940IDC, TNBCqRT-PCRprognostic factor for OStumor suppressorserum[138]
miR-1179BC not
classified
RT-PCRindependent prognostic
factor for OS
tumor
suppressor
breast tissue
not classified,
cell lines
[139]
miR-1247-5pBC not
classified
qRT-PCRindependent prognostic
indicator for DFS, OS
tumor
suppressor
FFPE, fresh
frozen tissue,
cell lines
[140, 141]
miR-1260BC not
classified
microRNA
arrays, qRT-
PCR
potential prognostic factor
for OS
onco-miRplasma[34]
miR-1274aBC not
classified
microRNA
arrays, qRT-
PCR
potential prognostic factor
for OS, PFS
onco-miRplasma[34]
miR-1274bBC not
classified
microRNA
arrays
potential prognostic factor
for DFS
onco-miRFFPE,
interstitial
breast tumor
fluids, serum
[68]
miR-1825BC not
classified
microRNA
arrays
potential prognostic factor
for DFS
onco-miRFFPE,
interstitial
breast tumor
fluids, serum
[68]
miR-3178BC not
classified
qRT-PCR,
microarray
associated with
poor response and
chemotherapy resistance
onco-miRFFPE, cell lines[75]
miR-4653-3pHR+ BC
(stage I~III)
qRT-PCRpotential prognostic
biomarker for DFS for
patients treated with
adjuvant tamoxifen
tumor
suppressor
FFPE[142]
miR-6780bBC not
classified
qRT-PCR,
microarray
associated with
poor response and
chemotherapy resistance
onco-miRFFPE, cell lines[75]

Table 2: List of prognostic microRNA signatures in breast cancer

miRNA signatureBreast cancer typeDetection methodPrognostic valueRoleBiological sampleReferences
miR-183-5p,
miR-194-5p,
miR-1285-5p
signature
BC not
classified
microarrays,
qRT-PCR
potential
prognostic
factor for OS
in young breast
cancer patients
(age <35 years)
miR-183-5p onco-miR
miR-194-5p onco-miR
miR-1285-5p tumor
suppressor
FFPE[48]
miR-21, miR-
30c, miR-181a,
miR-181c,
miR-125b,
miR-7, miR-
200a, miR-
135b, miR-22
and miR-200c
signature
HR
positive,
HER2
negative
qRT-PCRpotential
prognostic
factor for DRFS
10-miRNA-based
classifier as a
prognostic model
FFPE[49]
miR-155, miR-
493, miR-30e
and miR-27a
signature
TNBCqRT-PCR, IHCpotential
prognostic
factor for OS
associated
with taxanes
resistance
miR-155 tumor
suppressor
miR-493 tumor
suppressor
miR-30e onco-miR
miR-27a onco-miR
FFPE[50]
miR-16, 155,
125b, 374a
signature
TNBCqRT-PCRpotential
prognostic
factor for OS
miR-16 tumor
suppressor
miR-155 tumor
suppressor
miR-125b onco-miR
miR-374a tumor
suppressor
FFPE[51]
miR-16, 125b,
374a, 374b,
421, 655, 497
signature
TNBCqRT-PCRpotential
prognostic
factor for DDFS
miR-16 tumor
suppressor
miR-125b onco-miR
miR-374a tumor
suppressor
miR-374b tumor
suppressor
miR-421 onco-miR
miR-655 onco-miR
miR-497 tumor
suppressor
FFPE[51]
miR-191-5p,
miR-214-3p,
miR-451a,
and miR-489
signature
BC not
classified
qRT-PCR,
microarray
independent
prognostic
factor for OS,
DFS
miR-191-5p onco-miR
miR-214-3p tumor
suppressor
miR-451a tumor
suppressor miR-489
tumor suppressor
FFPE, cell lines[52]

According to our results, presented in Table 1, the majority of publications have not taken into account the distinct breast cancer subtypes during the development of their research protocol, since in 60.8% of studies breast cancer samples were not classified. The remaining 25.8% focused on Triple Negative Breast Cancer (TNBC) samples or involved Luminal A (5.0%), Luminal B (1.7%) and HER2-positive (1.7%) breast cancer samples. Of note, 5.0% of the selected studies accessed the prognostic value of miRNAs through experiments performed on breast cancer cell lines. Different detection methods, as well as different sample types were used for the detection of the prognostic miRNA expression levels (i.e., paraffin-fixed, formalin-fixed, freshly frozen tumors, plasma or serum). Concerning the detection methods, quantitative reverse transcriptase real-time polymerase chain reaction (qRT-PCR) was used in 35,8% of the eligible studies, while in 21,7% of the studies qRT-PCR was performed along with Microarray analysis. Additionally, next generation Sequencing technologies (9,2%), in situ hybridization techniques (9,2%), luciferase report assays (6,7%) or a combination of various techniques (10,8%) were employed.

DISCUSSION

We conducted a comprehensive systematic literature review to unfold the utility of miRNA biomarkers that can be evaluated for predicting prognosis in breast cancer patients. We have identified 117 studies that investigate the potential correlation between miRNA profile expression in breast cancer tissue and in the circulation and their possible use as prognostic factors. Interestingly, most of the miRNAs found to be associated with prognosis in breast cancer, were assessed in only a single study. Six miRs (miR-10b, miR-200b, miR-21, miR-203, miR-375, and miR-210) were evaluated in at least four studies and the discussion will be mainly focused on these molecules, based on an effort to merely provide some important information on the most commonly researched molecules in accordance with our systematic literature review.

MiR-21 is one of the most extensively studied cancer-related miRNAs and its aberrant expression and deregulation may play a pivotal role in the majority of cancers [14]. miR-21 may serve as a key regulator of oncogenic processes, including tumor growth, migration, and invasion [15], through targeting the pro-apoptotic phosphatase and tensin homolog (PTEN) and promoting tumor cell proliferation [16]. According to our initial search results, we retrieved 12 studies [16-27] and four meta-analyses [28-31] focusing on the prognostic value of miR-21, which collectively provide robust evidence that miR-21 up-regulation is associated with poor outcomes in cancer patients.

Mir-210 has multiple functions in cancer cells and is involved in angiogenesis, cell cycle regulation, DNA damage repair, mitochondrial metabolism, and immune response [32]. According to our search results, including seven studies [33-39], high expression of miR-210 has been significantly associated with poor survival in patients with breast cancer. Notably, single miR-210 assay has been proposed as an independent prognostic factor in this disease.

Concerning miR-10b, it has been presented as a potential biomarker that could play a predictive role in lymph node metastases occurrence across TNBC and in the incidence of high-grade tumors in non-TNBC cases [17]. Elevated expression of miR-10b in breast tumor tissue samples has been associated with adverse outcome, which is further supported from data derived from in vitro studies [40]. Finally, a survival analysis of 230 breast tissue samples has shown that high levels of miR-10b result to a short relapse free survival (RFS) of breast cancer, acting as an independent prognostic factor of RFS [41]. Our results, emphasize the oncogenic role of miR-10b and indicate that its high expression may be correlated with poor survival in breast cancer, while a recent metanalysis further strengthens our findings [30].

MiR-200 family members function as regulators of the epithelial to mesenchymal transition (EMT), which is one of the initial steps in tumor metastasis [42]. Specifically, miR-200b and miR-203 have both been characterized as tumor suppressors in multiple breast tumor types [43]. However, there seems to be an inconsistency in the existing literature, since we retrieved two studies that have found that higher expression of circulating miR-200b and miR-203 are associated with worse outcome [33, 34], further substantiated by a study on breast cancer cell lines [44]. However, other studies on breast cancer tissue samples and cell lines presented inverse results [45-47]. These discrepancies exhibit the diverse regulatory roles of miR-200 family members, depending on the cellular context and type of biological sample (blood VS tissue), and highlight the potential prognostic impact of these EMT regulating miRNA molecules in breast cancer.

Furthermore, our search retrieved five studies that have found six miRNA signatures to be useful for predicting the outcome of breast cancer [48-52]. Coordinated regulation of multiple miRNAs of potential prognostic value, has helped researchers identify panels of prognostic microRNAs for breast cancer. The discovery of microRNA expression signatures shows considerable promise for determining the prognosis of individuals with breast cancer. Similar miRNA signatures have been identified in a variety of other cancers, including acute myeloid leukemia, chronic lymphocytic leukemia, colon cancer, pancreatic cancer, and non-small cell lung cancer [53]. These reports highlight that this class of RNA molecules is showing substantial potential to be used as prognostic biomarkers for cancer.

Among the limitations of this effort, it should be stressed that this process was essentially driven by the search algorithm, which focused mainly on titles of the published literature, in an effort to provide more relevant results. Furthermore, clear heterogeneity was observed in our results, due to differences in patient characteristics (ethnicity, age, tumor stage, grade and subtype) and the use of different isolation and detection methods, cut-off values for miRNA expression levels, sample preparation methods and sample types (i.e., paraffin-fixed, formalin-fixed, freshly frozen tumors, plasma or serum).

Based on the results of this systematic review, we consider that miRNA detection may address the need for independent, easily accessible, prognostic molecular markers for breast cancer management in clinical practice, by assessing the impact of aberrant miRNA expression on patients’ survival. Our work sums up all the available data on prognostic miRNAs and can also act as a valuable reference point for future studies. Furthermore, while prognostic studies can assist in answering important questions concerning specific patient outcomes, their vigorous and careful design is a necessary condition for ensuring the reliability of results [54]. It should be stressed out that the thorough validation of prognostic factors is a necessary and unavoidable process in order to maximize certainty in predicting future breast cancer patients’ outcomes. Therefore, extensive validation studies focusing on particular miRNAs or miRNA signatures should be performed to relate baseline clinical and experimental variables to outcome. Eventually, all the reviewed molecular studies may help in bringing prognostic miRNAs closer to the clinical practice.

Materials and Methods

Methods of search strategy and study eligibility

This systematic review was conducted in accordance with the PRISMA guidelines [55] and in line with the a priori protocol agreed on and signed by EZ and FZ. Eligible studies were sought in PubMed without any restriction of publication language; the end-of-search date was January 28, 2019. The following search algorithm was used: breast[ti] AND (carcinoma OR carcinomas OR cancer OR cancers OR neoplasm OR neoplasms) AND (microRNA[ti] OR miR[ti] OR miRNA[ti] OR microRNAs[ti] OR miRs[ti] OR miRNAs[ti]) AND (prognosis[ti] OR prognostic[ti] OR survival[ti] OR outcome[ti] OR mortality[ti]). Eligible articles included studies examining the prognostic role of microRNAs in breast cancer. Only prospective and retrospective studies as well as case reports were considered eligible. In instances where multiple (overlapping) publications stemming from the same study were identified, the larger size study and the one with longer follow-up were included, unless the reported outcomes were mutually exclusive. Authors working independently and blindly to each other in pairs (E.Z., F.Z.) performed the selection of eligible studies; in case of disagreement, consensus with the whole team was reached.

Data extraction

The extraction of data comprised general information, including the name of the miRNA molecule, the breast cancer type in which its expression was determined, method of detection, the sample type that was used, its prognostic value in breast cancer, its function in cancer (onco-miR or tumor suppressor-miR) and the author-year of publication. Data were independently extracted and analyzed by a pair of reviewers (E.Z. and F.Z.), with one reviewer being blinded to the other; if needed, the final decision was reached by a team consensus.

Eligible literature met the following criteria: (1) measured miR expression levels in tumor or blood samples or human cell lines and (2) only articles in English. Publications were excluded if they had one or more of the following criteria: (1) studies referring to the prognostic role of single nucleotide polymorphisms (SNPs) in miRNA genes affecting their function; (2) studies that refer to the prognostic role of target miRNA molecules (molecules regulated by miRs); (3) studies based solely on a bioinformatics approach or a computational algorithm, with survival data originated from databases without subsequent biological validation and (4) review papers, meta-analyses, comments, letters or duplicate publications.

CONFLICTS OF INTEREST

The authors declare that they have no potential conflicts of interest.

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