International Journal of Biological Macromolecules 224 (2023) 1541–1565

Contents lists available at ScienceDirect

International Journal of Biological Macromolecules

journal homepage: www.elsevier.com/locate/ijbiomac

Review

Beneficial and detrimental aspects of miRNAs as chief players in breast

cancer: A comprehensive review
Ahmed Ismail a, Hesham A. El-Mahdy a, Ahmed I. Abulsoud a, c, Al-Aliaa M. Sallam b,
Mahmoud Gomaa Eldeib a, Elsayed G.E. Elsakka a, Mohamed Bakr Zaki d, Ahmed S. Doghish b, *
a
Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
b
Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
c
Department of Biochemistry and Biotechnology, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
d
Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Menoufia 32897, Egypt

A R T I C L E I N F O A B S T R A C T

Keywords: Breast cancer (BC) is the most common cancer in women and poses a serious threat to their health. Despite
Breast cancer (BC) familiarity with factors affecting its etiology, initiation, progression, treatment strategies, and even resistance to
Oncogenic miRNAs therapy, it is considered a significant problem for women. However, several factors have greatly affected pre­
Tumor suppressor (TS) miRNAs
vious aspects affecting BC progression and treatment in the last decades. miRNAs are short non-coding RNA
sequences that regulate gene expression by inhibiting the translation of the target mRNA. miRNAs play a crucial
role in BC pathogenesis by promoting cancer stem cell (CSCs) proliferation, postponing apoptosis, continuing the
cell cycle, and endorsing invasion, angiogenesis, and metastasis.
Similarly, miRNAs influence important BC-related molecular pathways such as the PI3K/AKT/mTOR signaling
pathway, the Wnt/β-catenin system, JAK/STAT signaling pathway, and the MAPK signaling pathway. Moreover,
miRNAs affect the treatment response of BC to chemo and radiotherapy. Consequently, this review aims to
provide an acquainted summary of oncomiRs and tumor suppressor (TS) miRNAs and their potential role in BC
pathogenesis and therapy responses by focusing on the molecular pathways that drive them.

Abbreviations: ABCG2, ATP binding cassette subfamily G member 2; ACVR1, Activin A receptor type 1; AGO, Argonaute; ALDH, aldehyde dehydrogenase; ALK1,
activin receptor-like kinase 1; ASPP2, apoptosis-stimulating protein of p53; ATM, ataxia telangiectasia mutated; Bak1, Bcl-2 antagonist killer 1; BCSCs, breast cancer
stem cells; BC, breast cancer; BRCA1, breast cancer 1; CAFs, cancer-associated fibroblasts; CAV1, caveolin 1; CS, citrate synthase; CXCL1, C-X-C motif chemokine
ligand 1; DGCR8, DiGeorge syndrome critical region 8; E2F2, E2F transcription Factor2; EGFR, epithelial growth factor receptor; EMT, epithelia-mesenchymal
transition; ERK, extracellular signal-regulated kinase; ERM, Ezrin/Radixin/Moesin; EVs, extracellular vesicles; EXP 5, exportin 5; EYA1, EYA transcriptional coac­
tivator and phosphatase 1; FBXW7, F-Box and WD repeat domain containing 7; FOXO3a, Forkhead Box O3a; HIF-1a, hypoxia-inducible factor 1-alpha; HOXA9,
Homeobox A9; HSF1, heat shock factor 1; IGF-1R, insulin-like growth factor type 1 receptor; IL-6, interleukin-6; JAK, Janus-activated kinase; LATS2, large tumor
suppressor kinase 2; LBR, Lamin B receptor; lncRNA, long ncRNA; LYVE1, lymphatic vessel endothelial hyaluronan receptor-1; LZTFL1, Leucine zipper transcription
factor-like 1; m7G, 7-methylguanosine; MAPK, mitogen-activated protein kinase; mTOR, mechanistic target of rapamycin; miRNAs, microRNAs; NACT, neoadjuvant
chemotherapy; ncRNA, non-coding RNA; NF-κB, nuclear factor kappa B; NK, natural killer; NPAT, nuclear protein of the ataxia-telangiectasia mutated locus; NPs,
nanoparticles; PCR, pathologic complete response; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; PDX, patient-derived tumor xenograft; PI3K,
phosphoinositol 3 kinase; piRNAs, interacting Piwis RNA; PK, pyruvate kinase; p-NPAT, phosphorylated-NPAT; PP2B-B1, protein phosphatase2B-B1; PPARG,
peroxisome proliferator activated receptor gamma; PTGS2, prostaglandin-endoperoxide synthase2; p-YAP, phospho-Yes-associated protein; RAB5B, Ras-related
protein Rab-5B; RECK, reversion inducing cysteine-rich protein with Kazal motifs; RGS3, regulator of G protein signaling 3; RISC, RNA-induced silencing complex;
RNF6, ring finger protein 6; RUNX3, RUNX family transcription factor 3; SCD1, stearoyl desaturase1; SerpinB2, serpin family B member 2; SFRPs, secreted frizzled
receptor protein; ShRNA, short hairpin RNA; siRNA, small interfering RNA; SLC7A11, solute carrier family 7 members 11; snoRNAs, Small nucleolar RNAs; SOCS,
suppressor of cytokine signaling; SOX, sry box; SP, side population; STAT, signal transducer and activator of transcription; STC, stanniocalcin 2; TGF-β, transforming
growth factor-β; TNBC, triple-negative BC; TRADD, TNFRSF1A-associated through death domain; TS, tumor suppressor; UTRs, untranslated regions; VEGFR2,
vascular endothelial growth factor receptor2; WASF3, Wiskott-Aldrich syndrome protein family member 3; WBP2, WW domain-binding protein 2; WIF1, Wnt
inhibitory factor-1; WT1, Wilms' tumor 1.
* Corresponding author.
E-mail address: [email protected] (A.S. Doghish).

https://doi.org/10.1016/j.ijbiomac.2022.10.241
Received 18 August 2022; Received in revised form 12 October 2022; Accepted 24 October 2022
Available online 1 November 2022
0141-8130/© 2022 Elsevier B.V. All rights reserved.
A. Ismail et al. International Journal of Biological Macromolecules 224 (2023) 1541–1565

1. Introduction using these key words (Breast cancer) or (BC), (Micro RNAs) or (miR­
NAs), (Biogenic pathways), (Breast cancer pathogenesis), (Breast cancer
Breast cancer (BC) is a prominent reason of morbidity, disability, and signaling pathways), (miRNAs in clinical application) and (miRNAs as
mortality in women, worldwide and poses a serious hazard to their therapeutic target). Besides, a manual search from the bibliography of
health [1]. In 2020, BC became the most diagnosed cancer overall, all included articles was performed to identify any relevant and eligible
exceeding lung cancer for the first time. Globally, it is also the main articles.
cause of cancer deaths among females in 110 countries, accounting for
15.5 % of cancer-related deaths. BC is the most predominant malig­ 2. miRNAs biogenic pathways
nancy, with >7.7 million women living 5 years from diagnosis [1,2].
Insight into the key players and the molecular mechanisms of BC Multiple coordinated processes and particular biological mecha­
metastasis is important because BC is prone to relapse and metastasize to nisms are required for miRNA biogenesis [20]. The post- or co-
many vital organs, such as lungs, brain, liver, and bone, causing patients' transcriptional processing of RNA polymerase II/III transcripts is the
death [3,4]. Despite significant progress in the early detection and beginning point for miRNA biogeny [33]. miRNAs are mostly tran­
treatment of BC, some patient groups appear to have worse outcomes scribed from introns and a few exons of protein-coding genes and are
[5]. Cell survival, division, and adaptation are highly reliant on the presumed intragenic. The other miRNAs are either intergenic, which
interaction of cellular proteins and RNA in a complex way [6]. Only 5 % means they are produced independently of a host gene and controlled by
of the human genome's function is known, while the rest is still being their promoters, or transcribed as a single lengthy transcript termed
researched and studied [7]. clusters, which may contain similar seed regions and are referred to as a
Non-coding RNA (ncRNA) can be divided into two types: long ncRNA family [21,34]. Both the canonical and non-canonical routes are
(lncRNA), containing >200 nucleotides, and short ncRNA, consisting of important for miRNA biogenesis. The canonical one is the more common
a chain of fewer than 200 nucleotides, containing small interfering RNA [35].
(siRNA), small nuclear RNAs (snRNAs), interacting Piwis (piRNAs), and
microRNAs (miRNAs) [8]. Both ncRNAs are critical participants in 2.1. The canonical pathway of miRNA biogenesis
various illnesses [9,10].
Despite its short length, ranging from 17 to 25 small single-stranded The canonical pathway is the most often employed miRNA process­
nucleotides, miRNAs play an important role in regulating gene expres­ ing mechanism. The microprocessor complex transforms pri-miRNAs
sion [11]. Approximately 35 % of the entire human genome is under into pre-miRNAs by combining an RNA-binding protein called
regulation by miRNAs [12]. The interaction of miRNAs with the 3′ un­ DiGeorge Syndrome Critical Region 8 (DGCR8) with a ribonuclease III
translated regions (UTR) of mRNAs is mostly used to regulate expres­ enzyme named Drosha [36]. DGCR8 recognizes an N6-methyl-
sion. In addition, gene promoters, 5′ UTR, and coding sequences are adenylated GGAC in pri-miRNA, while Drosha splits the pri-miRNA
targets with which miRNAs have also been reported to interact [13,14]. duplex at the base miRNA's hairpin shape. Consequently, a two nucle­
It also appears to regulate the rate at which translation and even tran­ otide 3′ overhang arises on pre-miRNA [37,38].
scription occur when they transfer between subcellular compartments Pre-miRNAs are generated and then exported to the cytoplasm via an
[15]. exportin 5 (EXP 5)/RanGTP complex, where the Dicer processes them.
Within a nematode called Caenorhabditis elegans, the first miRNA The terminal loop is removed in this stage, resulting in a mature miRNA
component, lin-4, was discovered, later playing a pivotal role in larval duplex [36] (Fig. 1).
development [16,17]. Next, the research moved to the rest of the living The two strands defined by the resulting miRNA duplex may be
model systems and found that miRNAs are highly conserved across organized into the protein family Argonaute (AGO), designated
species. Many miRNAs have been discovered, and new members are AGO1–4, in an ATP-dependent manner [39]. Following the synthesis of
constantly being discovered, highlighting their relevance and involve­ the miRNA duplex, one strand of the miRNA connects with an RNA-
ment in gene regulation [18–20]. induced silencing complex (RISC), establishing the “regulatory miR-
miRNAs are essential for various biological processes such as RISC complex.” The choice of 5p or 3p strands is determined by the
reproduction, differentiation, maturation, and metabolism and are thermodynamic stability of the 5′ UTRs at the nucleotide's 1-position
essential for the normal development of animals [21–23]. Alteration in [40]. The unoccupied strand, referred to as the passenger strand, is
miRNA expression leads to many metabolic disorders [24,25]. The loosened by various components of the loaded strand, referred to as the
altered expression may also occur in various disorders, with remarkable guide or leading strand, depending on their complementarity [41].
modifications in tumor tissues [26,27]. miRNAs profile has been linked
to the biomolecular classification of cancer [28,29]. Furthermore, 2.2. Non-canonical pathway of miRNA biogenesis
because miRNAs are released into body fluids such as urine, serum or
plasma, cerebrospinal fluid, and tears, they could be useful non-invasive Several non-canonical pathways for miRNA biogenesis have been
biomarkers to identify many disorders and tumors [30,31]. discovered and described. These pathways use a unique mix of proteins
Early and accurate diagnosis are the cornerstones that improve the used in the canonical pathway, including Drosha, exportin 5, Dicer, and
BC's therapeutic outcome and are the healthcare team's most important AGO2 [10]. Generally, the non-canonical miRNA biogenesis pathways
goals and those interested in health economics. Tumor tissues often may be classified as Drosha/DGCR8-independent or Dicer-independent.
express abnormal miRNA profiles, and specific miRNA alterations can be The Pre-miRNAs generated in the absence of Drosha/DGCR8 resemble
used to diagnose and stratify patients into subgroups with different Dicer substrates. Mirtrons are an example of such pre-miRNAs; they are
prognoses for personalized treatment [32]. synthesized from the introns of messenger RNA during splicing [42].
The present review summarizes the miRNAs' biogenic pathways and Another example is the pre-miRNA with a 7-methylguanosine (m7G)
aims to highlight the crucial contribution of various oncogenic and cap. Without the requirement for Drosha cleavage, these RNAs are
tumor suppressor (TS) miRNAs in regulating BC biological processes, immediately exported through exportin-1to the cytoplasm. There is a
molecular mechanisms, and therapeutic resistance. Moreover, the po­ substantial 3p strand bias, which is most likely caused by the m7G cap,
tential role of miRNAs as therapeutic targets will be addressed. which prevents the 5p strand from being loaded into AGO [43].
The strategy of constructing this review depends on an online search, Alternatively, Drosha processes Dicer-independent miRNAs from
for published research articles and various types of reviews, in the En­ endogenous short hairpin RNA (shRNA) transcripts. Due to their inad­
glish language, within the past 10 years, in different scientific search equate length to be Dicer substrates, these pre-miRNAs require AGO2 to
engines and d databases such as EMBASE, ScienceDirect, and PubMed by complete their development inside the cytoplasm, resulting in loading

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the entire pre-miRNA into AGO2 and 3p strand slicing dependent on The miR-155 is an oncogenic miRNA that is highly expressed in
AGO2. Trimming the 5p strand 3′ -5′ completes their development various solid tumors [53,54]. The miR-155 promotes the formation and
[44,45]. proliferation of the BCSCs by targeting ATP-binding cassette subfamily
G member 2 (ABCG2), CD44, and CD90. The stimulation of signal
3. Role of miRNAs in BC pathogenesis transducer and activator of transcription (STAT) 3 by induction of miR-
155 in BC cells is mediated by the Janus-activated kinase (JAK) pathway
Short transcript miRNAs are among the most recently recognized and motivation of BC cells by the inflammatory cytokines interleukin-6
contributors to BC pathogenesis by modulating BC initiation, prolifera­ (IL-6) [55,56]. In BC, miR-181 has been identified as an oncogenic
tion, progression, and conferring resistance to main therapeutic classes miRNA and encourages self-renewal, proliferation, tumor growth, and
[46]. colony formation. The transforming growth factor-β (TGF-β) allows the
sphere-formation of BCSCs by upregulation of miR-181 and down­
regulating ataxia telangiectasia mutated (ATM). In BC, the breast cancer
3.1. Role of miRNAs in initiation, proliferation, and stemness of BC 1 (BRCA1) gene is a direct target of miR-181. Moreover, the miR-181/
BRCA1 axis theatres a crucial role in promoting BCSCs [57–59].
3.1.1. miRNAs influenced the stemness of BC The suppressor of cytokine signaling (SOCS) protein family, which
The cancer stem cells (CSCs) are a tiny group of tumor cells consists of eight members, including cytokine-inducible Src homology 2
responsible for the tumor's start, proliferation, and growth. CSCs are (SH2)-containing protein (CIS) and SOCS1–7, has been reported as
unique in that they may self-renew indefinitely, are dormant, and are feedback inhibitors of cytokine-induced JAK/STAT signaling. The
resistant to chemo and radiotherapy [47,48]. Breast cancer stem cells growth hormone (GH)/insulin-like growth factor axis was first thought
(BCSCs) endorse the BC's tumor initiation, proliferation, and chemo­ of as being a feedback inhibitor by SOCS2. Other SOCS members, like
therapeutic resistance [49]. It is recognized that most miRNAs have a SOCS1 and SOCS3, have their protein levels controlled by SOCS2, which
thoughtful role in initiating and proliferating numerous types of cancer amplifies the signaling that is governed by these SOCS proteins [60].
by regulating different signaling pathways [50] (Table 1). Furthermore, miR-203 was overexpressed in BC tissues and cell lines.
The upregulation of miR-4319 decreases the tumorigenicity and Also, it endorses the growth, proliferation, and self-renewal of the
stemness of BCSCs in triple-negative BC (TNBC) by overturning the E2F BCSCs. In vitro, anti-miR-203 overwhelms the proliferation of ER+ of BC
transcription Factor2 (E2F2) expression, which is crucial for the self- cells, expression of CSCs surface markers, and the formation of mam­
renewal of the stem cells. In contrast, the downregulation of miR-4319 mospheres in BC cell lines by inhibiting the suppressor of cytokine
enhances the self-renewal and sphere formation of the tumor in the signaling (SOCS) 3. SOCS3 has been identified as a direct miR-203
CSCs of TNBC via E2F2. Similarly, it encourages the initiation and target. In BC samples, SOCS3 expression is inversely related to miR-
metastasis of the tumor in vivo (Fig. 2 and Table 1). Moreover, increased 203 [49,61].
E2F2 expression could counteract the effect of miR-4319 on CSC self- Breast cancer stem cells-derived extracellular vesicles (EVs) were
renewal of TNBC [49,51]. Similarly, upregulation of miR-600 could found to promote miR-197 delivery to BC cells, inhibiting peroxisome
reduce the ability of BCSCs to self-renewal, promote differentiation of proliferator-activated receptor gamma (PPARG) expression on mRNA
BCSC, and diminish the proliferation by targeting stearoyl desaturase1 and protein levels leading to the facilitation of EMT and enhancement of
(SCD1) via constraining the signaling pathway of Wnt/β-catenin. When BC cellular progression and metastasis. Knocking down of miR-197
miR-600 is downregulated, Wnt/β-catenin signaling is active, allowing significantly opposed the enhancing effect of BCSCs EVs on BC cell
BCSCs to self-renew. When miR-600 is highly expressed, it endorses the growth and metastasis [62].
differentiation of BCSCs and prevents the production of the active Wnt Other miRNAs involved in the oncogenesis and proliferation of BC
[49,52].

Fig. 1. miRNA biogenesis pathway. RNA polymerase

II/III first transcribes a primary miRNA transcript
(Pri-miRNA); after that, it is processed by a nuclear
protein complex to generate a pre-miRNA, which is
subsequently exported to the cytoplasm. A protein
complex in the cytoplasm completes the processing of
the pre-miRNA to create a miRNA duplex. The RNA
Induced Silencing Complex (RISC) receives one
strand of the duplex and directs it to target mRNAs
for mRNA degrading or translational suppression.

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Table 1
Role of miRNAs in initiation, proliferation, and stemness of BC.
miRNAs Alteration The main function Targets System Ref.

miR-4319 ↓↓↓ Decreases the tumorigenicity, self-renewal, and stemness of E2F2 In vivo, in vitro [51]
miR-600 BCSCs SCD1, Wnt/β-catenin signaling In vivo [49,52]
pathway
miR-155 ↑↑↑ Promotes growth, proliferation, and self-renewal of the BCSCs ABCG2, CD44, CD90 In vivo, in vitro [55,56]
miR-181 BRCA1 In vivo [57,58]
miR-203 SOCS3 Tissues, in vitro [61]
miR-9 and miR- Nanog, Oct4, CD133 Tissues, in vivo, in [63]
221 vitro
miR-29a H4K20 Tissues, in vitro [64]
miR-197 PPARG In vitro [62]
miR-130-3p ↓↓↓ Reduces stemness, proliferation, and tumorigenicity of BCSCs RAB5B Tissues, in vivo, in [65]
vitro
miR-590-5p SOX2 In vivo, in vitro [67]
miR-140 ALDH1, SOX9 [68]
miR-941 ↑↑↑ Regulates the proliferation of BC cells PP2B-B1 [69]
miR-30b-5p Endorses growth, proliferation, and migration of BC cells ASPP2 Tissues, in vivo, in [70]
vitro
miR-4800 ↓↓↓ Regulate migration and invasion CXCR4, ROCK1, CD44, vimentin In vitro [102]
miR-135 ZNF217 Tissues, in vitro, in [103]
vivo
miR-1 Inhibits the survival, proliferation, and invasion of BC cells Bcl-2 In vivo, in vitro [73]
miR-192 CAV1 Tissues, in vitro [74]
miR-124 STAT3 Tissues, in vivo, in [76]
miR-193a WT1 vitro [77]
miR-148a-3p VEGF, IGF-IR In vivo, in vitro [85]
miR-190 Hinders angiogenesis and proliferation in BC STC2 [86]
miR-200 family IL-8, CXCL1 [87]
miR-101 Constrains tumor growth and proliferation of BC cells SOX2 [89]
miR-372 E2F1 Tissues, in vitro [90]
miR-32 ↑↑↑ Promotes the cell proliferation of BC FBXW7 [104]
miR-106a Bcl-2, Bax, ABCG2, RUNX3 [105]
miR-96 RECK, FOXO3a In vivo, in vitro [99]
miR-26b ↓↓↓ Inhibits BC proliferation PTGS2, SLC7A11 Tissues, in vitro [100,101]

Fig. 2. miR-4319 and miR-497 inhibit the growth of BC via downregulating E2F2 and cyclin E1. Upregulation of miR-4319 reduces the tumorigenicity and stemness
of BCSCs in triple-negative breast cancer via reversing the expression of the E2F transcription Factor2 (E2F2), which is required for stem cell self-renewal. Cyclin E1 is
miR-497's intended target. The miR-497 inhibits cell cycle progression at the G1 stage by targeting cyclin E1, which reduces the progression of BC.

are miR-9 and miR-221. It has been detected that miR-9 and miR-221 of the BCSCs markers Oct4, CD133, and Nanog [49,63]. The miR-29a
were upregulated in BC and improved the stemness and migration of was upregulated in BC cell lines, BCSCs, and tissues. The miR-29a hin­
BCSCs through snowballing the number of side population (SP) colonies. ders the expression of the suppressor SUV420H2, which encodes a his­
On the other hand, the knockdown of miR-9 and miR-221 in BC cells tone methyltransferase that precisely trimethylates H4K20 and thus
decreased the number of SP colonies, which decreased the invasion, promotes BCSCs. So, miR-29a is oncogenic in BC cells that target H4K20
tumor cell renewal, and migration of BC by diminishing the expression [49,64].

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On the other hand, miR-130-3p was downregulated in BC cell lines miR-193a is a downregulated TS in BC's cells and tissues. Upregulation
and tissues, indicating a TS miRNA. In BCSCs, upregulation of miR-130a- of miR-193a represses the colony formation, migration, and prolifera­
3p inhibited migration and cellular proliferation while also causing cell tion of BT549 and MDA-MB-231 cells. It also reduces the expression of
cycle arrest. Ras-related protein Rab-5B (RAB5B) is directly targeted and Wilms' tumor 1 (WT1). The expression of WT1 and miR-193 were
downregulated by miR-130a-3p. The Knockdown of the oncogenic inversely associated in BC tissues. miR-193a constrains metastasis and
RAB5B also repressed migration, invasion, and cell proliferation of proliferation of BC by directly targeting and downregulating the
BCSCs [65]. Sex-determining region Y-box 2, also known as SOX2, is a expression of WT1 [77].
transcription factor that is essential for maintaining self-renewal, or Angiogenesis is a complex and multi-step process to form novel blood
pluripotency, of undifferentiated embryonic stem cells. SOX2 is critical vessels from pre-existing ones. It initiates with the proliferating,
in maintaining embryonic and neural stem cells [66]. miR-590-5p is a TS migrating, and differentiating endothelial cells in reply to signals from
miRNA that is downregulated in BC cells. miR-590-5p dramatically nearby tissue, such as hypoxia. Vascular endothelial growth factor
diminished BCSCs population and proliferation and also inhibited (VEGF) promotes the development of new blood vessels. The primary
tumorigenicity. miR-590-5p downregulated the protein expression of forms of VEGF are A, B, C, and D; they control angiogenesis via binding
sry box-2 (SOX2) [67]. to VEGF tyrosine kinase receptors [78].
The miR-140 is one of the TS miRNAs in BC cells. It was down­ The tumor's ability to obtain a blood supply is fundamental to tumor
regulated in BCSCs when compared to normal stem cells. As a result, growth. It is an important step in tumor initiation. Similarly, VEGFs have
miR-140 downregulation promotes the development and proliferation a critical role in the proliferation and pathogenesis of various tumors
of BCSCs. In BC cells, aldehyde dehydrogenase 1 (ALDH1) and SOX9 [79–81]. Highly expression of the VEGF is determined in various solid
were reported to be targets of miR-140. So, the miR-140/ALDH1/SOX9 cancers such as BC. miRNAs are convincing mediators and regulators of
axis is hazardous to the tumor formation and self-renewal of BCSCs in VEGFs, which are the most protruding regulators of angiogenesis,
vivo [68]. dangerous for the proliferation and development of BC cells [82,83].
By a similar mechanism, miR-148a-3p acts as TS miRNAs that sup­
3.1.2. miRNAs influenced the initiation and proliferation of BC press BC's proliferation, angiogenesis, and tumor growth. A study stated
The initiation, proliferation, and carcinogenesis of human BC cells that melatonin increased the level of the miR-148a-3p gene and
are all strongly affected by miRNAs (Table 1). The miR-941 was diminished the gene and protein expression of VEGF and insulin-like
dramatically upregulated in MDA-MB-231 cells compared to MCF-10A growth factor type 1 receptor (IGF-1R), both in vivo and in vitro [84].
cells. Inhibition of miR-941 diminished the migration, growth, and The expression of hypoxia-inducible factor 1-alpha (HIF-1a), a tran­
proliferation of MDA-MB-231 cells by fluctuating the expressions of scription factor that regulates VEGF production, was diminished by miR-
Cyclin D1, p21, E-cadherin, and protein phosphatase2B-B1 (PP2B-B1). 148a. Consequently, miR-148a overwhelms angiogenesis in BC. The
Also, an inhibitor of miR-941 exhibited an important increase in the miR-148a Upregulation targets insulin receptor substrate-1, and IGF-IR
protein expression of PP2B-B1. So, PP2B-B1 was identified as a direct overpowers tumor angiogenesis of BC cells by overturning their down­
target of miR-941 in BC cells [69]. The miR-30b-5p is another oncogenic stream mitogen-activated protein kinase (MAPK)/extracellular signal-
miRNA upregulated in BC tissues and cell lines. The miR-30b-5p acts as a regulated kinase (ERK) and AKT pathways [85].
tumor promoter via direct targeting apoptosis-stimulating protein of p53 Angiogenesis, proliferation, and tumor growth were inhibited by
(ASPP2), leading to activation of the AKT signaling pathway [70]. overexpression of miR-190 in BC cells. The stanniocalcin 2 (STC2) was a
The BCL-2 family is divided into three groups based on their primary direct target of miR-190. The miR-190 upregulation reserved prolifer­
function (1) anti-apoptotic proteins (BCL-2, BCL-XL, BCL–W), (2) pro- ation and epithelial-mesenchymal transition (EMT), hindering the AKT/
apoptotic pore-formers (BAX, BAK, BOK) and (3) pro-apoptotic BH3- ERK signaling pathway through STC2 [86]. miR-200 family hinders
only proteins (BAD, BID, BIK) [71]. Bax and Bcl-2 are the major mem­ proliferation and angiogenesis via targeting C-X-C motif chemokine
bers of the Bcl-2 family and play a key role in tumor progression or in­ ligand 1 (CXCL1) and IL-8 produced by the tumor cells. Additionally,
hibition of intrinsic apoptotic pathways triggered by mitochondrial members of the miR-200 family have been revealed to suppress VEGF,
dysfunction. Therefore, the balance between pro- and anti-apoptotic which inhibited proliferation and angiogenesis [87,88].
members of this family can determine cellular fate [72]. SOX2 is one of the perilous oncogenes in several cancers. The
The miR-1 is a TS miRNA in BC. Overexpression of miR-1 constrains upregulation of SOX2 in BC's cell lines and tissues was allied with
BC's growth and proliferation and promotes the BC cell's apoptosis. In BC metastasis, increased proliferation, and tumor growth. miR-101 was
cells and tissues, miR-1 is expressed at low levels. The 3′ UTR of the Bcl-2 dramatically downregulated in cell lines and tissues of BC. Furthermore,
gene contains miR-1 binding sites. Bcl-2 was highly expressed in BC miR-101 overexpression suppresses BC cells in vitro and in vivo, whereas
tissues in contrast to normal breast tissues. It was found that miR-1 miR-101 downregulation has the opposite effect. SOX2 was identified as
down-regulated Bcl-2 expression at the mRNA and protein levels in a direct target of miR-101 in BC cells. The miR-101 obstructs prolifer­
MCF-7 and ZR-7530 cells. It was observed that the luciferase activities of ation, migration, and tumor growth and persuades BC Cells to apoptosis
the Bcl-2 vector were reduced following treatment with miR-1 mimics. by targeting SOX2 [89].
In addition, it was found that the expression level of miR-1 and Bcl-2 in The miR-372 has an imperative role in developing and initiating
BC tissues was negatively correlated. Which also demonstrated that Bcl- numerous human cancers. The expression level of miR-372 in BC tissues
2 might be a target of miR-1. This finding demonstrated that over­ and cell lines was dramatically diminished. Moreover, miR-372 impedes
expression of miR-1 inhibited cell migration and invasion, which is cell proliferation and encourages apoptosis in the BC cell line as MCF-7
reversed by Bcl-2 overexpression [73]. Also, miR-192 was down­ cells. miR-372 was directly targeting the E2F1 in BC cells. Knockdown of
regulated in BC cells compared to normal tissues. Upregulation of miR- E2F1 persuades apoptosis and hinders the proliferation in the MCF-7 cell
192 enhances cell apoptosis and cell cycle arrest and inhibits cell pro­ lines of BC [90].
liferation in MDA-MB-231 and MCF7 cells. Moreover, it was established Overexpression of miR-32 endorsed proliferation and repressed
that CAV1 is a target of miR-192. Consequently, miR-192 plays a crucial apoptosis. In contrast, the down expression of miR-32 exhibited a
role in regulating BC cell apoptosis and proliferation through the miR- reverse effect. The F-Box and WD repeat domain containing 7 (FBXW7)
192/CAV1 axis [74]. is a perilous TS that is a direct target of miR-32. Moreover, a reverse
The miR-124 acts as a TS by directly targeting the oncogene STAT3 association was found between the expressions of mRNA levels of
in BC [75]. When miR-124 targets STAT3, it leads to the inhibition of FBXW7 and miR-32 in BC tissues. Down expression or knockdown of
proliferation and invasion of BC cells. Overexpression of miR-124 di­ FBXW7 encourages tumor growth and proliferation and represses
minishes the mRNA of STAT3 and its protein levels in BC cells [76]. Also, apoptosis in MCF-7 cell lines [91].

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Another onco-miR in BC is miR-106a, which is dramatically over­ Numerous studies have confirmed the participation of miRNAs in the
expressed in human BC tissue. The miR-106a promotes invasion, tumor PTGS2 regulation, one of these miRNAs is miR-26b. So, overexpression
growth, and proliferation of BC cells through increased levels of ABCG2, of miR-26b hinders proliferation and cellular growth by directly tar­
Bcl-2, and decreased expression of Bax, P53, and RUNX family tran­ geting PTGS2. Also, miR-26b encourages apoptosis in the MCF-7 BC cells
scription factor 3 (RUNX3) [87]. Overexpression of miR-106a improved by targeting solute carrier family 7 members 11 (SLC7A11). Conse­
colony-forming capacity, tumor growth, migration, and proliferation of quently, miR-26b acts as a TS, whose dysregulation may be intricated in
BC cells. Furthermore, overexpression of miR-106a diminished BC cell human BC's initiation, tumor growth, and proliferation [100,101]. miR-
apoptosis. 4800 has been identified to be downregulated in BC. The restoration of
Upregulation of miR-96 was found in a diversity of tumors, such as miR-4800 in MDA-MB-231 cells resulted in the down-expression of
lung [92], prostate cancer [93], colorectal cancer [94], and BC [95]. CXCR4, ROCK1, CD44, and vimentin genes, restricting the proliferation
Additionally, the upregulation of miR-96 persuaded the proliferation in and migration of BC cells [102]. Similarly, miR-135 expression was low
MCF-7 BC cells by directly downregulating Forkhead Box O3a (FOXO3a) in BC tissues and cells, while zinc finger protein 217 (ZNF217) expres­
[95]. The reversion-inducing cysteine-rich protein with Kazal motifs sion was high. Subsequently, when the expressions of miR-135 and
(RECK), a TS gene, was targeted by numerous miRNAs, miR-182 [96], ZNF217 were reversed to evaluate their effects on BC cell migration,
miR-92a [97], and miR-21 [98] that were described to overwhelm the invasion, and EMT initiation. It was found that BC cell malignant be­
expression of RECK and act as onco-miRs. miR-96 was upregulated in BC haviors were significantly inhibited, which was reproduced in nude
cells and tissue compared to non-malignant cells and tissues. Over­ mice for in vivo evidence [103].
expression of miR-96 endorsed migration, cellular proliferation, and
invasion of BC cells, at least in part, by directly targeting RECK.
Furthermore, the oncogenic effects of miR-96 were mimicked by 3.2. Role of miRNAs in BC progression
silencing the RECK. So, miR-96 acts as an oncogenic miRNAs in BC [99].
On the contrary, miR-26b was downregulated in BC cells and tissues MiRNAs are non-coding RNA regulating post-transcriptionally genes
compared to normal ones, so miR-26b acts as a TS in BC cells. in various biological processes during BC advancement. The miRNAs
Prostaglandin-endoperoxide synthase2 (PTGS2) suppresses the immune bind specific mRNAs and suppress their expression by either mRNA
response, carcinogenesis, angiogenesis, and inhibition of apoptosis. destruction or inhibition of mRNA translation. Thus, various human BC
biological processes or the key stages of BC advancement have been

Table 2
miRNAs in BC progression.
miRNAs Alteration Cellular function Target System Ref.

miR-497 ↓↓↓ Cell cycle Cyclin E1 In vitro, clinical [108]

miR-30c-2-3p [109]
miR-483-3p In vitro [110]
miR-424 CDK1 [111]
miR-26a-5p RNF6/ERα/Bcl-xL [112]
miR-1207-5p ↑↑↑ STAT6, CDKN1A, and CDKN1B [113]
miR-206 WBP2 [117]
miR-639 p21Cip1/Waf1 Clinical, in vitro [118]
miR-135b LATS2/CDK2 and p-YAP [120]
miR-519a-3p Apoptosis TNFRSF10B, CASP8, CASP7 In vitro [123]
miR-191-5p SOX4, CASP3, CASP7 [124]
miR-204 ↓↓↓ JAK2, STAT3, BCl-2, survivin. Clinical, in vitro [125,126]
PTEN/PI3K/AKT signaling pathway
miR-148 BCl-2 Clinical, in vitro, in vivo [127]
miR-101 SOX2, EYA1 [89]
miR-192 CAV1 In vitro, clinical [74]
miR-615-5p HSF1 [167]
miR-32 ↑↑↑ FBXW7 [130]
miR-383-5p ↓↓↓ PD-L1 [131]
miR-101 Migration, EMT, invasion, and SOX2 [89]
miR-124a metastasis SerpinB2 Clinical, in vitro, in vivo [134]
miR-26b
miR-200c/141 ↑↑↑
cluster
miR-21 LZTFL1 [136]
miR-683 HOXA9/Wnt/β-cadherin Clinical, in vitro [137]
miR-10b TGF-EMT, HOXD10 Clinical [139]
miR-93 ↓↓↓ WASF3 In vivo, in vitro [140]
miR-200b ERM In vitro [135]
miR-340 Wnt/β-catenin In vitro, in vivo [141]
miR-148a [142]
miR-374a ↑↑↑ [143]
miR-122 PK, CS [145]
miR-222 LBR [146]
miR-215-5p ↓↓↓ Sox9 [147]
miR-let7d HIF1/PDGF/PDGFR axis [148]
miR-29b ↓↓↓ Angiogenesis Akt3, VEGF, c-MYC [161]
miR-140-5p VEGFA Clinical, in vitro, in vivo [162]
miR-126 In vitro [163]
miR-126-3p RGS3 [164]
miR-526b ↑↑↑ VEGFC, VEGFA, VEGFD, COX-2, EP4, VEGFR1, In vitro [165]
miR-655 VEGFR2
miR-199b-5p ↓↓↓ ALK1/Smad/Id1 pathway In vitro, in vivo [166]

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connected etiologically to abnormal miRNA expression. The miRNAs The BC progression is thought to be caused by ectopic expression of
can act as oncogenes or TSs for BC progression by affecting cellular non-coding RNAs. Yan et al. discovered that when estrogen was induced,
processes such as cell cycle maintenance, apoptosis retardation, raising MYC expression increased, resulting in the activation of PVT1, a long
angiogenesis, enhanced EMT, and metastasis [27,106]. This section was non-coding RNA in BC cells. Compared to normal controls, increased
classified into subsections to summarize the involvement of an updated levels of PVT1, the host gene of miR-1207-5p, significantly stimulated
list of miRNAs in cellular processes of BC advancement (Table 2). the expression of miR-1207-5p in BC samples. The percentage of cells in
the G2 phase of the cell cycle rose when the miR-1207-5p expression was
3.2.1. miRNAs affect the cell cycle during BC progression elevated, but inhibition of miR-1207-5p diminished cell viability.
Cell cycle transition maintains the intricate equilibrium between Increased levels of miR-1207-5p also inhibited STAT6 expression and
promoting and inhibiting cell proliferation. A finite number of cell di­ augmented cell cycle advancement via CDKN1A/B inactivation. These
visions is the major characteristic of normal non-cancerous cells, which two genes act as cell cycle suppressors [113] (Fig. 3 and Table 2).
is largely regulated. When a limiting cell density is reached, the arrest of The WW domain-binding protein 2 (WBP2) acts as a transcriptional
the cell cycle at the G0 phase start, and cells become inactive. In co-activator that could significantly increase ER/PR transactivation
contrast, the cancer cells lack this physiological regulation and do not [114,115]. In addition, the WBP2 promotes cancer-invasive features via
respond to the environment's inhibitory growth cues, resulting in the activation of TCF-mediated transcription, which is mediated by the
continued cell cycle progression and BC advancement. The miRNAs interaction between interact WBP2 and β-catenin. The WBP2 plays
regulate BC's cell cycle progression pathways [107]. important in cell cycle progression [116]. Consequently, in ER+ BC
For illustration, cyclin E1 is a key regulator of the G1–S transition in patients, increased WBP2 expression is linked to a higher risk of meta­
the cell cycle, and it's become a popular target for miRNAs in BC. The static recurrence (MR) and poor survival. In both MCF-7 and BT474
miR-497 has low expression in BC tissues than normal. The target of cells, upregulation of WBP2 helped the G1/S transition by altering the
miR-497 is cyclin E1. By targeting cyclin E1, miR-497 induces cell cycle expression of CDK4, cyclin D1, and p21 cell cycle-related genes. How­
arrest at the G1 stage, decreasing BC progression [108] (Fig. 2 and ever, WBP2 knockdown hindered cell cycle transition. In its 3′ UTR,
Table 2). Also, in vitro data demonstrate that miR-30c-2-3p targets the WBP2 has a conserved miR-206 binding site, in which the increased
cell cycle protein cyclin E1 and the TNFRSF1A-associated through the level of miR-206 inhibits the G1/S transition by targeting WBP2 [117]
death domain (TRADD). Elucidating that miR-30c-2-3p regulates the (Table 2).
cell cycle progression negatively and also the nuclear factor kappa B A clinical study carried out by Ismail et al. (2019) on miR-639 in BC
(NF-κB) signaling in BC. So, overexpression of miR-30c-2-3p by mimic patients found that miR-639 was overexpressed in BC patients compared
inhibits cell cycle progression and decreases invasion in triple-negative to control, and the increased level of miR-639 was linked to the pro­
BC. A study involving 781 breast tumors concluded that miR-30c-2-3p gression of BC [27]. The miR-639 acts via regulation of the p21Cip1/
has anti-tumor activity, and the good outcomes in BC are associated Waf1, a cell cycle regulator [118]. In addition, an in vitro investigation
with the overexpression of miR-30c-2-3p [109]. found that miR-639 upregulation leads to BC invasion and metastasis.
The NF-κB signaling is constitutively active in TNBC subtypes and is These findings establish molecular and clinical linkages between miR-
commonly uncontrolled in various cancers. The TNBC subtypes are 639 and BC, suggesting a vital function for miR-639 in BC metastasis
linked to a much worse overall life expectancy [109]. Similarly, the [119]. Also, the miR-135b in BC specimens and cells is higher than
study on miR-483-3p found that the miR-483-3p acted as a TS and was normal. The miR-135b targets the large TS kinase 2 (LATS2).
downregulated in BC. On the other hand, the overexpression of miR- Further research revealed that the miR-135b and LATS2 axis could
483-3p dramatically prevented the G1–S cell cycle transition in BC via influence downstream genes in the Hippo pathway, such as CDK2 and
direct targeting the cyclin E. Phospho-Yes-associated protein (p-YAP). Consequently, the forced pro­
In addition, the miR-483-3p is a direct target of cytokine E1, and the duction of miR-135b can disrupt the cell cycle, control migration, and
reduced cyclin E1 expression caused by the miR-483-3p overexpression invade BC. Moreover, LATS2 knockdown can mimic the effect of miR-
also stops the nuclear protein of the ataxia-telangiectasia mutated locus
(NPAT) and phosphorylated-NPAT (p-NPAT), a downstream target of
cyclin E1 [110]. The stop of the NPAT and p-NPAT “crucial nuclear
protein for cell cycle progression through the G1 and S phases and S
phase entrance leads to the prevention of BC entering the S-phase of the
cell cycle as a result of reduced DNA synthesis initiation. Furthermore,
the upregulation of miR-483-3p prevented the formation of a complex
involving cyclin E1 and the cyclin-dependent kinase CDK2, which reg­
ulates the cell cycle [110].
The miR-424 transcript was also decreased throughout many BC
specimens and cell lines. CDK1 and miR-424 have a direct connection.
According to the findings, miR-424 inhibits BC cells from entering the
G2/M cell phase by negatively regulating CDK1 mRNA. Consequently,
miR-424 has anti-oncogenic activity in BC and inhibits BC progression
[111]. Another miRNA that inhibits BC progression by regulating the
cell cycle is the miR-26a-5p which was significantly downregulated in
both BC cell lines and tissues. Down-regulation of miR-26a-5p in BC
patients has been linked to a poor prognosis.
On the contrary, the miR-26a-5p overexpression increased the
expression of TS protein p53, p21, and p27 and decreased the expression
of the cell cycle regulatory proteins such as Cyclin D1, CDK4, and CDK6
are among the proteins that inhibit the advancement of BC. The miR-
26a-5p conquers BC's RNF6/ER/Bcl-xL axis by directly affecting the
expression of the ring finger protein 6 (RNF6). Disobediently, the RNF6/ Fig. 3. miR-1207-5p promotes BC cell viability and cell cycle progression.
ERα/Bcl-xL axis is activated by the decreased miR-26a-5p expression Increased miR-1207-5p inhibited STAT6 expression and enhanced cell cycle
and enhances BC progression [112]. progression by inactivating CDKN1A/B (cell cycle genes suppressors).

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135b upregulation in BC, giving new insight into the therapeutic target but decreased the Bcl2, cyclin D1, and PCNA mRNA and protein
for BC [120]. expression. Hence, miR-615-5p may play a role in the advancement of
BC by targeting HSF1 [129].
3.2.2. miRNAs affect apoptosis during BC progression Still, miR-32 was highly expressed in BC tissue samples and cell lines.
When a normal cell's chromosomal or genetic contents are disrupted, The miR-32 upregulation inhibited apoptosis and enhanced prolifera­
a signaling cascade of apoptosis is triggered as a defense mechanism tion and migration via targeting FBXW7. Besides, miR-32 and FBXW7
[106]. On the other hand, cancer cells resist apoptosis, even when their mRNA levels in BC tissues were inversely related. The FBXW7 knocking-
genetic contents have been drastically altered. Any disruption of the down in MCF-7 cells boosted proliferation and motility while sup­
apoptotic cascade in mammary cells could lead to malignant trans­ pressing apoptosis [130]. Furthermore, miRNA dysregulation has been
formation and increased cell viability. Loss of the TS p53, caspase ac­ linked to immunological suppression mediated by PD-L1. In a study
tivity deregulation, increase of pro-survival regulators, reduced examining the relationship between miR-383-5p and PDL-1 in BC tissues
expression of pro-apoptotic proteins, and inactivation of death ligands and cell lines, researchers discovered that miR-383-5p was down­
have all been discovered to aid BC cells' resistance to apoptosis [121]. regulated while PDL-1 was increased in BC tissues. Furthermore, miR-
The apoptosis resistance in BC is regulated by miRNAs [122]. The 383-5p transfection induced BC apoptosis and inhibited BC invasion,
miR-519a-3p was substantially expressed in Advanced-grade BC with migration, and metastasis via the PI3K/AKT/mTOR pathway and inhi­
mutant p53 and was linked to a bad prognosis. Increased expression of bition of metastasis-related gene expression, modulating the expression
miR-519a-3p protected BC cells from apoptosis by direct down­ of apoptosis-related genes. Suggesting that the inhibitory effect of
regulation of target genes for TRAIL-R2 and caspase-8. Furthermore, the transfected miR-383-5p on the PI3K/AKT/mTOR pathway is the un­
miR-519a-3p inhibited tumor cell death by enabling BC to escape NK derlying mechanism for inhibiting tumoral PD-L1 [131] (Table 2).
cell recognition via downregulating the NKG2D ligands MICA and It was found that induced expression of miR-375 promotes tumori­
ULBP2 on the tumor cells required for detection by NK cells [123]. In genicity in the breast. Inhibition of miR-375 significantly inhibits cell
addition, the increased expression of miR-191-5p inhibited apoptosis in proliferation, triggers the generation of intracellular ROS, suppresses
MCF7 and ZR-75 BC cell lines, as evidenced by decreased caspase 3/7 cell migration, and induced apoptosis in MCF-7 breast cancer cells [132]
activity, whereas decreased expression of miR-191-5p had the opposite (Table 2).
effect. In MCF7 cells, SOX4 overexpression boosts p53 protein levels.
Overexpression of miR-191-5p resulted in a decrease in SOX4 and hence 3.2.3. miRNAs affect migration, EMT, invasion, and metastasis during BC
p53 levels, implying the existence of a regulatory feedback loop between progression
miR-191-5p-p53-SOX4 [124]. The miRNAs also play a critical role in BC progression via enhancing
Furthermore, a study on miR-204 found that both human BC tissue migration, EMT, invasion, and metastasis [133]. For illustration, miR-
and MCF-7, MDA-MB-231 cultured BC cell lines have significantly lower 101 expression was drastically reduced in BC tissues and cell lines.
levels of miR-204 expression. The miR-204 overexpression enhanced Downregulation of miR-101 increased BC progression. In contrast, in
apoptosis in BC cells, which was reversed by the co-transfection of a vitro and in vivo overexpression of miR-101 reduced the malignant ten­
miR-204 inhibitor. The miR-204 inhibits the activation of STAT3, BCl-2, dencies of BC cells via directly binding SOX2. Thus, miR-101, by directly
and survivin by targeting JAK2, suppressing JAK2 and p-JAK2 expres­ targeting SOX2, plays a significant role in BC suppression [89]. In
sion in BC [125]. In another investigation, the miR-204 expression was addition, SerpinB2 upregulation in the TNBC subtype was significantly
found to be downregulated in BC cell lines. In the MCF7 BC cell line, related to metastatic risk in BC and also linked to poor outcomes in BC
overexpression of miR-204 decreased cell proliferation by triggering patients. Tumor spreading and poor outcomes have been connected to
apoptotic cell death and cell cycle arrest in the G2/M phase. MCF7 BC the miR-200 family.
cells were likewise prevented from migrating and invading when miR- Upregulation of the miR-200c/141 cluster influenced the metastatic
204 was overexpressed. The miR-204 acts by targeting PTEN. Because ability of BC cells by inducing the expression of serpin family B member
PTEN regulates the PI3K/AKT signaling pathway, the effect of miR-204 2 (SerpinB2). The miR-26b and miR-124a, which target SepinB2, were
overexpression on this system was investigated, and it was discovered likewise downregulated in BC. In a xenograft mouse model, increasing
that miR-204 overexpression strongly reduces the production of p-AKT levels of miR-200c/141 promoted lymph node and lung metastasis, but
and p-PI3K in MCF7 BC cells [126]. These data indicated that miR-204 SerpinB2 knockdown reversed the miR-200c/141-induced metastasis.
regulates BC progression by inducing cell cycle arrest and apoptosis and Hence, SerpinB2 could be a valuable biomarker for determining the
decreasing metastatic potential [125,126] (Table 2). likelihood of metastasis in BC patients [134]. In addition, miR-200b
Likewise, the TS miR-148a, downregulated in BC cells and tissues, is regulates Ezrin/Radixin/Moesin (ERM), a possible biomarker for BC
associated with apoptosis. The miR-148 overexpression decreased BC progression. The miR-200b was downregulated in BC, resulting in the
cell survival while increasing apoptosis and inhibited tumor growth in elevation of ERM, leading to enhanced invasion and migration. In
vivo via direct suppression of BCL-2 [127]. Furthermore, miR-101, which contrast, transfection of miR-200b mimic decreased ERM and inhibits
targets SOX2, causes death in BC cells in vitro and in vivo resulting in BC progression [135] (Table 2).
decreased BC growth, proliferation, and migration [89]. Transfection of In clinical/in vitro/in vivo investigations on BC patients and cell lines,
a miR-101 mimic increased apoptosis via decreasing EYA transcriptional miR-21 was overexpressed in BC patients more than in the control. The
coactivator and phosphatase 1 (EYA1) expression, whereas miR-101 level of miR-21 decreased after surgery compared to pre-surgery.
inhibitor transfection resulted in the opposite. Also, miR-101 increases MicroRNA-21 inhibition inhibited cell proliferation and metastasis in
apoptosis via Notch signaling pathways by negatively affecting EYA1 BC cells via targeting The Leucine zipper transcription factor-like 1
[128]. (LZTFL1). Furthermore, LZTFL1 knocking-down reversed the inhibitory
In MCF7 and MDAMB231 BC cells, overexpression of miR-192 effect of miR-21 on cell proliferation, metastasis, and EMT marker
caused cell death and cell cycle arrest via targeting caveolin 1 CAV1, expression in BC cells. In vivo, increased expression of miR-21 increased
which was identified as a possible target of miR-192 using a bioinfor­ BC cell growth and metastasis [136].
matics method. As a result, miR-192 plays an important function as a Moreover, miR-638 was downregulated in BC, accompanied by a bad
regulator of BC progression, and the miR-192/CAV1 axis may be a po­ prognosis. In contrast, increased miR-638 expression inhibited BC's
tential therapy for BC [74]. In the diseased tissues of BC patients, the viability, migration, and invasion. The miR-638 directly binds to the
miR-615-5p is reduced. Heat shock factor 1(HSF1) is directly targeted by Homeobox A9 (HOXA9), which is overexpressed in BC. In BC, HOXA9
the miR-615-5p mimic, which increases apoptosis in BC cells. The miR- overexpression can reduce miR-638 anti-tumor impact, and miR-638
615-5p mimics transfection increased Bax mRNA and protein expression can block the Wnt/β-cadherin pathway and EMT. As a result of its

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binding to HOXA9, miR-638 slows the course of BC [137]. Also, a miR-222 overexpression. Overexpression of miR-222, or knockdown of
clinical study carried out on the Egyptian population by Ismail et al. [27] LBR, was enough to cause NFs to exhibit CAF features such as increased
to explore the role of miR-10b in BC indicated that miR-10b was over­ motility and metastasis [146].
expressed in metastatic BC patients more than in healthy control. The These behaviors in fibroblasts were reduced by reverse changes in
miR-10b acts as an oncogenic miRNA in BC and is associated with the CAFs, as were paracrine actions on BC cells. This data indicated that
advancement of BC and poor outcomes [27]. The miR-10b is associated miR-222/LBR plays an important role in regulating the pro-progression
with the advancement marker, such as HER-2 overexpression. Further­ effects of CAFs in BC [146]. miR-215-5p works as a TS in BC by directly
more, Ismail et al. [27] demonstrated that miR-10b in BC had a sensi­ targeting the SRY-Box 9 (Sox9) gene. When compared to non-tumor
tivity of 78.3 % and a total accuracy of 83.75 % compared to the routine tissue, the miR-215-5p is significantly down-expressed in BC. Accord­
biomarkers, CA-15.3 and p53 had a sensitivity of just 48.3%and 55 %, ingly, Sox9 knockdown duplicates miR-215-suppressive 5p's effects on
respectively. Hence miR-10b could be a useful biomarker for detecting BC cells, while overexpression of Sox9 rescues miR-215-effects 5p's on
BC in its early stages [27]. Mechanistically, miR-10b through TGF-EMT BC cell development. In addition, miR-215-5p suppresses BC cell pro­
targeting has been linked to increased BC migration and invasion [138]. liferation and metastatic potential in vivo, according to a xenograft
Also, miR-10b, which the Twist transcription factor regulates, binds to model experiment. These findings suggest that miR-215-5p inhibits BC
the HoxD10 gene, suppressing the Ras homolog gene family and mem­ cell aggression by targeting Sox9 [147].
ber C protein and promoting BC metastatic spread [139]. Brain metastasis is a common late consequence in individuals with
The CSCs are cancer cells that induce primary tumor development metastatic BC, whose poor prognosis necessitates the development of
and distant metastases [48]. Epigenetic changes, especially those new and more effective treatments. In a recently established model of BC
mediated by miRNAs, are strongly linked to the acquisition of CSC metastasis, active HIF1 signaling and loss of the miRNA let-7d cooperate
characteristics. The expression levels of miR-93 in the miR-106-b/25 to promote brain metastasis. Increased expression of PDGF B/A in
cluster in CD44+ human cancer cells metastasized to the liver were human brain metastasis cells is caused by active HIF1 and loss of let-7d.
substantially lower than at the primary site in previously established BC HIF1 and PDGF-A/B silencing or let-7d overexpression, on the other
patient-derived tumor xenograft (PDX) mouse. Subsequently, in vitro, hand, inhibited brain metastases formation [148]. Accordingly, Let-7d
overexpression of miR-93 inhibited BC cells' ability to invade, and in silencing boosted HIF1 expression and activity, according to a regula­
vivo, it greatly reduced their ability to spread to the liver. Additionally, tory hierarchy of the system. In the 4T1-BM2 model, treatment with
the Wiskott-Aldrich syndrome protein family member 3 (WASF3), a nilotinib, a kinase inhibitor that inhibits PDGF receptor (PDGFR)
regulator of CSC characteristics, was a functional target of miR-93. signaling, inhibited the creation of spontaneous brain metastases and
Overexpression of miR-93 decreased the protein level of WASF3 in BC reduced the size of established brain metastases in human and mouse
cells, and WASF3 reversed the miR-93-mediated inhibition of BC cell models. These findings point to active HIF1 signaling and loss of let-7d
invasion. These data imply that miR-93 acts as a metastasis suppressor in as coordinated events that promote BC brain metastasis by increasing
breast tumors by inhibiting invasion and CSC characteristics [140]. PDGF-A/B expression. Further, PDGFR inhibition is also a viable ther­
In addition, Wnt/β-catenin signaling has been established as a major apeutic option for patients with brain metastasis [148].
regulator of EMT and BC metastatic pathways. The discovery that some EYA1 was found to be a target of miR-622. When the expression of
miRNAs play a significant role in the Wnt/− catenin signaling pathway miR-622 was upregulated, the expression levels of EYA1 were signifi­
sheds light on the molecular foundations of BC metastasis. The TS miR- cantly decreased on mRNA and protein levels. The increased expression
340 inhibits BC cell motility, invasion, and metastasis by targeting the of miR-622 significantly enhanced the proliferation, migration, and in­
Wnt/β-catenin signaling cascade [141]. Likewise, miR-148a was vasion of the MCF-7 cell line [149]. Tumor-associated macrophages
downregulated in BC cells and tissues. Overexpression of miR-148a by (TAMs) promote cancer cell proliferation, immunosuppression, and
mimics diminished BC cell motility and invasion via WNT-1, a ligand in metastasis. Li et al. estimated the role of extracellular vesicles loaded
Wnt/β-catenin signaling. The miR-148a overexpression lowered the miR-660 derived from TAMs in BC and its target Kelch-like Protein 21
expression of several important components of the Wnt/β-catenin (KLHL21), particularly in metastasis. They found that KLHL21 was
pathway, including β-catenin, MMP-7, and TCF-4 and WNT-1 mRNA and poorly expressed, whereas miR-660 was highly expressed in breast
protein levels, resulting in inhibition of BC metastasis [142]. cancer tissues and cells. They concluded that extracellular vesicles
In contrast, in BC cells increased level of miR-374a activates the loaded with miR-660 promote cancerous cell invasion and migration
Wnt/β-catenin pathway leading to augmenting BC metastasis via [150].
increasing EMT [143]. Furthermore, abnormal miR-374a decreased the
level of epithelial indicators such as E-cadherin, β-catenin, and CK18, 3.2.4. miRNAs and breast cancer metastasis to bone
increasing mesenchymal markers such as vimentin and N-cadherin According to a large body of research, miRNAs are intimately linked
elucidating its critical role in EMT, distant metastasis in BC cells. The to the behavior of breast cancer cells and the development of bone
Wnt inhibitory factor-1 (WIF1), PTEN, and WNT5A were among the metastases. For instance, miR-429 has been demonstrated to suppress
negative regulators of the Wnt/β-catenin signaling pathway that miR- bone metastases in vivo and to decrease proliferation, migration, inva­
374a directly targeted and repressed [143] (Table 2). sion, and EMT in breast cancer cells [151]. In addition, overexpression
Another tool that enhances BC metastasis and invasion is metabolic of miR-30b-d, miR-30b-c, or miR-30a-b-c-d-e resulted in a decreased
reprogramming, which plays an important role in BC progression and ability of the MDA-B02 bone metastatic breast cancer cell line to invade
treatment responses [145]. The metabolic reprogramming is controlled [152]. Others have demonstrated how transglutaminase 2 (TG2) inhibits
by miRNAs and thus alters the expression of miRNAs in enhancing BC miR-205 in breast cancer cells, encouraging bone metastasis [153]. In
metastasis. Increased level of miR-122 was ascribed to reprogramming addition, miR-203 and miR-135 overexpression decreased the migra­
of glucose metabolism, leading to enhanced metastasis in vitro and in tory, proliferative capacity, and survivability of breast cancer cells in
vivo via downregulation of pyruvate kinase (PK) and citrate synthase vitro, and decreased tumor growth in bone was seen in vivo [154].
(CS) [145]. Disseminated breast cancer cells can undergo a process called
Cancer-associated fibroblasts (CAFs) are involved in the invasion and osteomimicry, in which they take on a phenotype resembling that of
metastasis of cancer. The CAFs have higher levels of miR-222. The CAF- bone cells, increasing their likelihood of surviving in bone [155]. Runt-
like expression profiles were promoted by ectopic miR-222 expression in related transcription factor 2 (Runx2), Bone Morphogenetic Proteins
NFs, whereas CAF traits were suppressed by miR-222 knockdown in (BMPs), Alkaline Phosphatase (ALP), PTHrP, RANKL, or OPG are ex­
CAFs. Lamin B receptor (LBR) was a direct miR-222 target, and it was amples of osteomimicry factors expressed by breast cancer cells that
found to be functionally important because LBR knockdown mimicked adhere to the bone; these are covered in great depth in [156].

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Interestingly, miRNAs can influence the expression of a number of genes by regulating ALK1 expression. The overexpression of miR-199b-5p
connected to osteomimicry in breast cancer cells, which may explain stopped HUVECs from forming capillary-like tubular structures or
how they regulate metastasis. For instance, Dickkopf-related protein 1 migrating via ALK1 inhibition. Furthermore, the upregulation of miR-
and osteomimetic genes CX43 and CDH11 were decreased by over­ 199b-5p in HUVECs reduced the activation of the ALK1/Smad/Id1
expressing miR-30s in MDA-B02 cells (DKK1) [157]. In contrast, miR- pathway by BMP9. Finally, in vivo, upregulation of miR-199b-5p
218 boosted the expression of the chemokine receptor CXCR4 and the inhibited tumor development and angiogenesis [166] (Table 2).
proteins bone sialoprotein (BSP), osteopontin (OPN), and bone sialo­ We can state that miRNAs act as an important regulator of the
protein (BSP) in MDA-MB-231 breast cancer cells [158], suggesting that cellular process involved in BC progressions, such as cell cycle,
miR-218 supports osteomimicry and, thus, breast cancer cells homing to apoptosis, migration, invasion, EMT, metastasis, and angiogenesis.
the bone. Consequently, illustrating and targeting altered miRNA expression may
Additionally, miRNAs have a direct impact on osteoclast differenti­ help understand the causes of BC poor outcomes and might help develop
ation. For instance, osteoclast differentiation and/or activity were new treatment regimens.
decreased in vitro when miR-141, miR-190, miR-219, miR-33a, and miR-
133a were expressed ectopically [159]. Overexpression of miR-218 in 3.3. Role of miRNAs in BC resistance to the major treatments
breast cancer cells promotes bone metastases through both direct and
indirect effects on osteoblasts, according to research by Liu et al. [160]. In the last decade, miRNAs have been widely reported to have a role
The scientists described two distinct methods through which miR-218 in the sensitivity or resistance of cancer to treatment, including
may influence bone metastases in breast cancer. First, compared to the chemotherapy [168], radiotherapy [169], hormonal therapy [170], or
parental cell line, bone metastatic breast cancer cells release EVs that immunotherapy [171].
have higher amounts of miR-218 [160].
3.3.1. Hormonal therapy
3.2.5. miRNAs affect angiogenesis during BC progression Hormonal therapy is the most used adjuvant therapy in treating BC,
Concurrently, angiogenesis is another process that plays an impor­ mainly receptor-positive ones as (HR+) and HER2 negative. It exerts its
tant role in BC progression by creating new blood vesicles via VEGF. The action either by reducing hormone levels or competing for binding on
miRNAs regulate angiogenesis-related genes. For instance, ectopic the same receptors [172]. The most frequent hormone-based drugs used
expression of miR-29b inhibits angiogenesis by targeting Akt3 and de­ include fulvestrant, tamoxifen, LH-releasing hormone analogs, and
creases VEGF and C-myc activity. In vivo, it results in significant tumor aromatase inhibitors [173].
growth inhibition. But the expression of miR-29b was downregulated in It's reported that some miRNAs could contribute resistance to
BC [161]. The miR-140-5p is another miRNA that regulates angiogenesis hormones-related BC therapy as miR-221/222 and miR-155, among
and has been linked to a worse prognosis in metastatic cancer tissues. In others. Upon activation of β-catenin, miR-221/222 contributes to
vitro and in vivo, miR-140-5p increased expression by a miRNA mimic estrogen-independent growth. Besides, they also inhibit TGF-β-mediated
transfection reduced angiogenesis by suppressing VEGFA expression and growth. The 2 previous actions could finally lead to fulvestrant resis­
other proteins like Ki-67, CD31, and MMP-9 [162]. tance [174]. Besides their role in fulvestrant resistance, miR-221/222
In addition, compared to control cells, miR-126 was overexpressed in was also reported to mediate tamoxifen resistance through reduced
treated MCF7BC cells. The miR-126 expression has been linked to ERα protein expression [175] (Table 3).
reduced cell proliferation and the arrest of MCF7 cells in the G1 phase In a case-control study on BC patients luminal-subtype who had
via VEGF-A, which is regarded as a functionally important and direct undergone anti-hormonal therapy for at least 1 year, the expression level
target of miR-126 in the MCF7 BC cell line [163]. Further, miR-126-3p is of miR-221 was higher in tamoxifen-resistant BC cases, and hence the
downregulated in TNBC cell lines. Overexpression of miR-126-3p miR-221 was concluded to be a potential marker of tamoxifen resistance
impaired cell invasion, migration, and colony formation capacity (P < [176].
0.001) by suppression of the regulator of G protein signaling 3 (RGS3), Cell survival and tamoxifen resistance are induced by ectopic
which was confirmed as a direct target of miR-126-3p in TNBC. Hence, expression of miR-155, while inhibition of miR-155 enhances cell
miR-126-3p acts as a TS by targeting RGS3, implying that the miR-126- apoptosis and tamoxifen sensitivity [155]. It was also reported that miR-
3p/RGS3 axis could be a possible therapy target [164]. 155 exerts its action through its effect on SOCS6. SOCS6 is inhibited at
Both miR-655 and miR-526b are associated with angiogenesis and mRNA and protein levels if miR-155 is overexpressed continually. On
metastasis under the induction by COX-2. Ectopic overexpression of the other hand, its expression is stimulated upon miR-155 knockdown
miR-655 and miR-526b in poorly metastatic ER-positive MCF7 BC cells [177] (Table 3). Apart from tamoxifen resistance, tamoxifen sensitivity
led to the upregulation of angiogenesis markers. Furthermore, angio­ is correlated with miR-375 expression. miR-375 down-regulation is
genesis and metastasis are augmented in miR-rich conditioned media, observed in tamoxifen-resistant cells. This resistance was abolished
accompanied by increased levels of VEGFR1, VEGFR2, and EP4 upon miR-375 re-expression, an action that was accompanied by a
expression, representing miRNA paracrine activation in the tumor partial reversal of EMT [178]. Finally, aromatase inhibitors are also
microenvironment. EP4 antagonists of PI3K/Akt inhibitor treatments affected by miRNAs. Masri et al. reported that letrozole-resistant cell
prevented miR-induced migration and tube formation, indicating that lines are resensitized upon miR-128a inhibition. This effect contributed
the EP4 and PI3K/Akt pathways are involved. PTEN, a TS gene, was to the resensitization of the cell lines to TGFβ growth inhibitory effects
downregulated in miRNA high cells, indicating that both miRNAs target [179] (Table 3).
it. PTEN suppresses HIF1 and the PI3K/Akt pathway, which increases
VEGF expression when these pathways are not regulated by PTEN [165]. 3.3.2. Chemotherapy resistance
Furthermore, expression of angiogenesis markers VEGFA and VEGFD Chemotherapy uses cytotoxic medicines to destroy tumor cells or
was significantly higher in breast tumors, and expression of miR-526b reduce their proliferation rates. Chemotherapy is an important choice in
and miR-655 in BC samples was positively correlated with VEGFA/D the treatment of BC [180]. Like hormone-related therapy, BC's response
and CD31 expression. These findings support miRNAs as BC biomarkers to chemotherapy also correlates with some miRNA expression. Tormo
and EP4 as a possible therapeutic target for preventing miR-induced et al. [181] have reported that better survival in doxorubicin-treated BC
angiogenesis [165]. patients was associated with elevated levels of miR-449a, an effect that
The endothelial cells have a higher level of activin receptor-like ki­ was suggested to be due to the involvement of miR-449a in doxorubicin
nase 1 (ALK1), an important angiogenesis regulator. The miRNAs act as resistance. Moreover, miR-192-5p overexpression increases the sensi­
modulators of angiogenesis and therapeutic targets for cancer treatment tivity of BC cell lines to doxorubicin. This effect was suggested due to

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Table 3
Role of miRNAs in BC resistance to the major treatments.
miRNA Alteration Effect on treatment Target System Ref.

miR-221/222 ↑↑↑ Increases the resistance to fulvestrant B catenin In vitro [174]

TGFB
miR-221/222 ↑↑↑ Increases the resistance to tamoxifen Affect ERα protein expression In vitro [175]
miR-155 ↓↓↓ Increase the sensitivity to tamoxifen Affect SOCS6 protein and mRNA In vitro [177]
miR-375 ↑↑↑ Decreases resistance to tamoxifen Downregulation of MTHD causing EMT In vitro [178]
reversal
miR-128a ↓↓↓ Resensitizes letrozole-resistant cell lines Resensitization of the cells to TGFβ In vitro [179]
growth inhibitory effects
miR-449 ↑↑↑ Increase the survival in doxorubicin treatment Cell cycle factors In vivo [181]
miR-192-5p ↑↑↑ Decrease the resistance to doxorubicin JNK, BAD caspase9 PPIA and Bcl-2 In vitro [182]
miR-181a ↑↑↑ Increase the resistance to doxorubicin Decrease BAX expression In vitro [183]
miR-451 ↑↑↑ Increase the sensitivity to doxorubicin Regulation of multidrug resistance gene In vitro [184]
1
miR-130a ↑↑↑ Decrease doxorubicin resistance In vivo and in [185]
vitro
miR-21 ↑↑↑ Increase doxorubicin resistance Decrease PTEN expression In vitro [186]
miR-149-5p ↑↑↑ Decrease the resistance to paclitaxel MyD88 In vitro [241]
miR-5195-3p ↑↑↑ Decrease the resistance to paclitaxel EIF4A2 In vitro [187]
miR-335-5p let- ↑↑↑ Increase the taxanes resistance CXCL9, CCR7, and SOCS1 In vitro [188]
7c-5p
miR-17 ↓↓↓ Increase taxanes resistance NCOA3 upregulation In vitro [189]
miR-20b
miR-125b ↑↑↑ Increases taxol resistance Bak1 In vitro [190]
miR-205 ↑↑↑ Increase sensitivity to TAC regimen Suppression of VEGFA and FGF2 In vitro [191]
Modulate HOXD9-Snail1 In vitro [242]
miR-223 ↑↑↑ Increases the resistance to platinum-based therapy Associated with increased expression of In vivo [194]
EGFR
miR-452 ↓↓↓ Increase the resistance to adriamycin Insulin-like growth factor-1 receptor In vitro [195]
miR-210 ↓↑ Positively correlates with trastuzumab sensitivity, tumor presence, and In vivo [202]
lymph node metastases
miR-21 ↑↑↑ Increase resistance to trastuzumab Decease PTEN gene expression In vitro [203]
Silence the TS gene PDCD4 In vivo [204]
miR-125a ↑↑↑ Decrease trastuzumab resistance Increased HER2 protein expression In vitro [205]
miR-125a-3p ↑↑↑ Exhibits a synergistic effect on trastuzumab In vivo [205]
miR-770-5p ↑↑↑ Enhance trastuzumab anti-tumor activity Inhibits PI3K/AKT/mTOR pathways In vitro [206]
miR-542-3p ↓↓↓ Increase trastuzumab resistance Stimulate AKT activity In vitro [207]
miR-770-5p ↑↑↑ Increase sensitivity to radiotherapy (Through regulation of some PBK In vitro [213]
miR-671-5p downstream target genes involved in cells growth and invasion) FOXM1 In vitro [214]
miR-449-5p HSPA1A In vivo [215]
In vitro
miR-200c STXBP4 In vivo [216]
In vitro
miR-129-5p HMGB1 In vitro [217]
miR-125b Jun-1 In vivo [218]
In vitro
miR-634 STAT3 In vitro [219]
miRNA124 In vivo [220]
miR-7 EGFR/PI3K/Akt1 In vitro [221]
miR-302 ↑↑↑ Increase sensitivity to radiotherapy (Through regulation of cell cycle and RAD52 In vitro [222]
DNA repairs) In vivo
miR-185 In vitro [223]
miR-205 ZEB1 In vitro [224]
In vivo
miR-15 Chk1 and Wee1 In vitro [225]
miR-155 RAD51 In vitro [226]
In vivo
miR-139-5p RAD54L In vitro [227]
In vivo
miR-200c Chk1 In vitro [228]
In vivo
miR-200c ↑↑↑ Increase sensitivity to radiation through their effects on autophagy-related UBQLN1 In vitro [229]
genes In vivo
miR-129-5p HMGB1 In vitro [217]
miR-200c ↑↑↑ Increase sensitivity to radiation through regulation of apoptosis pathway TBK1 In vitro [230]
miR-27a Cdc27 In vitro [231]
miR-22 Sirt1 In vitro [232]
miR-148 Caspase 3 In vitro [233]
Tissue from
patients
miR-142-3p ↑↑↑ Increase sensitivity to radiation Reduce BC stem cells In vitro [235]
miR-95 ↑↑↑ Increase sensitivity to radiation Promote cell growth, invasion, and In vitro [237]
metastasis In vivo
miR-144 In vitro [238]
miR-620 In vitro [239]
In vivo
miR-668 In vitro [240]

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JNK activation, BAD and caspase 9 expression stimulation, and inhibi­ inhibitors or monoclonal antibodies that can specifically target proteins
tion of PPIA and Bcl-2 expression [182]. On the other hand, Niu et al. or genes involved in cancer pathways [196], including monoclonal an­
reported that stimulation of miR-181a enhances doxorubicin resistance tibodies such as trastuzumab [197], atezolizumab [198], and pertuzu­
through decreased BAX expression [183]. However, doxorubicin resis­ mab [172], Palbociclib [199], ribociclib [200] and mTOR inhibitors as
tance was abolished upon miR-451 transfection to MCF-7/DOX-resistant everolimus [201] and alpelisib [200].
cells [183], an effect that was interpreted by the regulatory effect of Several reports have indicated that targeted therapy success might be
miR-451 on the expression of the multidrug resistance 1 gene [184] correlated to miRNA levels. The circulating miR-210 level was corre­
(Table 3). lated with trastuzumab sensitivity, tumor presence, and lymph node
The miR-130a and miR-21also have an impact on doxorubicin metastases. These results suggest that plasma miR-210 might be used to
treatment. Huang et al. [185] reported that the miR-130a upregulation predict and monitor response to trastuzumab therapies [202]. Besides,
level reduced cell viability and colony number and reversed doxorubicin BC tissue expression of miR-21 is correlated with resistance to trastu­
resistance in MCF-7/Adr cells (Table 3). Besides, in the breast tissue of zumab therapy [203]. Huang et al. reported that miR-21 silences the TS
BC patients, the miR-130a level was higher after neoadjuvant chemo­ gene PDCD4 at the mRNA level leading to the stimulation of metastatic
therapy than that before neoadjuvant chemotherapy. Moreover, the potential [204]. In triple-negative BC cell lines, miR-125a over­
expression of miR-130a is significantly higher in tumor tissues of pa­ expression is associated with better therapeutic results. It increased the
tients sensitive to neoadjuvant therapy than those of resistant patients. sensitivity of the BC cell lines to Trastuzumab, an effect that may be
Regarding miR-21, it was reported that its upregulation imparts resis­ attributed to increased HER2 protein expression and decreased migra­
tance to doxorubicin, an effect that may be due to targeting PTEN [186] tion of triple-negative BC cells [205]. Regarding in-vivo studies, miR-
(Table 3). 125a-3p has a synergistic effect on trastuzumab in HER2-expressing
Besides the role of miRNAs in doxorubicin resistance, they also have TNBC cells in mice [205] (Table 3).
an important role in the response of cancer cells to taxanes, adriamycin, Besides the effect of miR-125a-3p, trastuzumab's anti-tumor activity
and platinum-based therapy. miR-149-5p and miR-5195-3p were re­ has also been reported to be enhanced by miR-770-5p. It inhibits PI3K/
ported to reverse paclitaxel resistance. Where miR-149-5p was reported AKT/mTOR pathways and downregulates HER2 expression [206].
to increase tumor sensitivity by suppressing the MyD88 expression Alternatively, AKT activity is stimulated by miR-542-3p downregulation
[165]. The miR-5195-3p reverse paclitaxel resistance by targeting leading to trastuzumab resistance in vitro [207] (Table 3).
EIF4A2 [187]. Chen et al. [188] have confirmed the regulatory effect of Because HER2+ BCs respond poorly to the targeted therapy, the
miR-335-5p and let-7c-5p on taxanes-resistance. They reported the close Expression levels of miR-101-5p were determined in HER2+ breast
relationship of the downstream genes of the 2 miRNAs (CXCL9, CCR7, tumor and adjacent normal samples, and its ability to sensitize HER2+
and SOCS1) with taxane resistance. miR-17 and miR-20b are also BC cells KPL4 for the treatment with tucatinib, lapatinib and trastuzu­
involved in taxane resistance. Their downregulation upregulates NCOA3 mab was evaluated. Results showed that miR-101-5p significantly
promoting BC resistance [189] (Table 3). down-expressed in tumor tissues compared to normal tissue. Treatment
On the other hand, miR-125b was reported to be upregulated in of KPL4 cells by lapatinib or trastuzumab did not affect either apoptosis
Taxol-resistant cells, causing a marked suppression of Taxol-induced or proliferation, while cotreatment with miR-101-5p sensitized cells to
apoptosis and cytotoxicity. This effect may be attributed to the direct both lapatinib and trastuzumab [208]. Overexpression of miR-145
effect of miR-125b on pro-apoptotic Bcl-2 antagonist killer 1 (Bak1). improved the sensitivity of BC cells to docetaxel in vivo and in vitro
Down-regulation of Bak1 inhibits Taxol-induced apoptosis and increases through inhibition of the PI3K/AKT pathway, while the inhibitor of miR-
Taxol resistance. Restoring Bak1 expression by either miR-125b inhib­ 145 decreased this sensitivity [209].
itor or re-expression of Bak1 in miR-125b-overexpressing cells restored
Taxol sensitivity [190]. Moreover, miR-205 was reported to enhance the 3.3.4. Resistance to radiotherapy
chemosensitivity of BC cell lines to TAC (docetaxel, doxorubicin plus Radiotherapy is one of the options standardized in managing BC,
cyclophosphamide), a widely used neoadjuvant chemotherapy. This especially after surgery, to decrease the chance of local recurrence
action is due to the suppression of both VEGFA and FGF2, leading to the [210]. Radiotherapy could kill cancer cells or decrease their prolifera­
evasion of apoptosis [191]. Lin et al. reported another mechanism for tive capacity [211]. Regarding radiotherapy resistance, miRNAs may
the effect of miR-205 on BC resistance to chemotherapy. They reported induce sensitivity or resistance to ionizing radiation. The radio-
that miR-205 could modulate HOXD9-Snail1 to inhibit triple-negative sensitizing-inducing miRNAs enhance cancer cell death following
BC chemoresistance and proliferation [192] (Table 3). ionizing radiation, while radioresistant-inducing ones could induce the
The tumor suppressor gene BRCA1 was predicted to be a target for miR- cancer cells to switch to other pathways that allow the cell to survive
199a-3p. The effects of miR-199a-3p-mediated BRCA1 suppression on following irradiation [212] (Table 3).
the progression of TNBC and chemosensitivity to cisplatin and veliparib Many miRNAs were reported to induce radio-sensitivity through
were assessed using MDA-MB-231 and MDA-MB-468 as in vitro model regulation of some downstream target genes involved in cells growth
and Mouse xenograft model for in vivo study. The miR-199a-3p targeted and invasion as, PBK (miR-770-5p) [213], FOXM1 (miR-671-5p) [214],
BRCA1 directly in TNBC cells, leading to its downregulation. Over­ HSPA1A (miR-449-5p) [215], STXBP4 (miR-200c) [216], HMGB1 (miR-
expression of miR-199a-3p in TNBC cells showed inhibitory effects on 129-5p) [217], Jun-1 (miR-125b) [218], STAT3 (miRNA124 and miR-
cell proliferation and migration in vitro and xenograft tumor growth in 634) [219,220] and EGFR/PI3K/Akt1 (miR-7) [221] (Table 3).
vivo. In addition, overexpression of miR-199a-3p was shown to diminish Besides downstream target genes involved in cell growth and inva­
cisplatin-resistance and sensitize TNBC cells to veliparib [193]. sion, some miRNAs were reported to exert their activities through cell
In Indonesian TNBC patients, the elevation of miR-223 was linked to cycle regulation and DNA repairs leading to increased sensitivity of BC
higher EGFR expression, a bad prognosis, and resistance to platinum- cells to irradiation. These miRNAs include miR-185 and miR-302
based chemotherapy [194]. On the other hand, Hu et al. [195] found (RAD52) [222,223], miR-205 (ZEB1) [224], miR-15 family (Chk1 and
that miR-452 is significantly down-regulated in MCF-7 cells resistant to Wee1) [225], miR-155 (RAD51) [226], miR-139-5p (RAD54L) [227]
Adriamycin. This resistance may be due to the targeting of insulin-like and miR-200c (Chk1) [228]. On the other hand, some miRNAs could
growth factor-1 receptors (Table 3). affect autophagy-related genes, such as miR-200c (UBQLN1) [229] and
miR-129-5p (HMGB1) [217]. Finally, radiosensitivity could be gener­
3.3.3. Resistance to targeted therapy ated through regulation of apoptosis and cell death pathways as and
Immune or targeted therapy has been developed as an alternative to miR-200c (TBK1) [230], miR-27a (Cdc27) [231], miR-22 (Sirt1) [232]
BC treatment. It depends on using agents such as small-molecule and miR-148 (Caspase 3 protein) [233] (Table 3).

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The effects of miR-93-5p on proliferation, migration, apoptosis, and On the other side, miR-96 functions as an oncogenic by promoting
radiosensitivity were investigated in BC cells. MDA-MB-468, MCF-7, and cellular growth and metastasis in BC [250]. The miR-93 stimulates cell
MDA-MB-231 BC cells by Pan et al. showed that miR-93-5p restricts BC proliferation by directly targeting PTEN in BC [251] (Fig. 4A). The miR-
cell proliferation and migration and enhances the apoptosis radiosen­ 221 overexpression has been observed in many advanced BC. Increased
sitivity of BC cells [234]. miR-221 expression confers increased cancer aggressiveness, metastasis,
Cancer stem cell generation [210], apoptosis inhibition, and and chemo-resistance [252] (Table 4).
increased cell growth [211] are important mechanisms contributing to
cancer resistance to therapy. miR-142-3p overexpression was reported 4.2. Wnt/b-catenin signaling pathway
to reduce BC stem cells in-vitro [235]. Interestingly, miR-142-3p was
reported to be upregulated upon CD44 silencing leading to enhanced Aberrant activation of Wnt/b-catenin signaling was related to tumor
sensitivity of BC cells to doxorubicin [236]. Other miRNAs that are re­ progression and poor prognosis in BC patients. Various studies revealed
ported to promote cell growth, invasion, and metastasis include miR-95 oncogenic miRNAs could endorse Wnt signaling by suppressing negative
[237], miR-144 [238], miR-620 [239], and miR-668 [240] (Table 3). effectors such as GSK-3 β, APC, and ICAT proteins [253]. Overexpressed
miR-1229 induces Wnt/β-catenin signaling by targeting GSK-3 β and
4. The interplay between miRNA and signaling pathways in BC APC [254]. The upregulation of miR-1301 was related to aggressive
features and poor prognosis in patients with BC by downregulating ICAT
4.1. PI3K/AKT/mTOR signaling pathway expression [255] (Fig. 4B).
The miR-125b is another overexpressed Wnt/β-catenin signaling
The mechanistic target of the rapamycin (mTOR) complex comprises pathway regulatory miRNA in BC [256]. It targets the 3´-UTR of APC,
two portions, mTORC1, and mTORC2. The miRNAs are involved in consequently induces Wnt/β-catenin signaling, and is correlated with
mTORC1 and regulate cell metastasis, proliferation, cell cycle, and tumor development and dissemination [256].
apoptosis by directly or indirectly targeting genes [243]. Some miRNAs The expression of GSK-3 β protein was inhibited by miR-3646 and
directly target mTOR, whereas others modulate mTOR signaling via associated with docetaxel resistance and upregulation of β-catenin
targeting other pathway components like PI3K and AKT [244]. [257]. Increased expression of miR-29a was reported to downregulate
Many miRNAs act as TSs by targeting the mTOR pathway. On one GSK-3 β and PTEN resulting in Adriamycin resistance in the BC cell. The
side, miR-122 is a TS in BC, and its increased expression prevents BC cell miR-3646 and miR-29a are drug resistance inducers in breast tumor
growth by targeting two major signaling molecules of mTOR signaling, cells [258]. Additionally, WIF1 was repressed via miR-374a, which is
PI3CG and IGF1R [245] (Fig. 4A). Additionally, miR-99 suppresses upregulated in patients with metastatic BC [143].
mTOR expression by targeting its 3-UTR [246]. Likewise, miR-204 β-Catenin was identified as the target gene for some regulatory
genomic loci are lost in BC, targeting mTOR [247]. Similarly, miR- miRNAs downregulated in breast tumor cells. The miR-135 was a TS that
125b can suppress the expression of mTOR, thus inhibiting BC prolif­ inhibits cell proliferation and EMT by regulating GSK3- β via inhibition
eration and reducing drug resistance [248]. The downregulation of of Wnt/b-catenin [259] (Fig. 4B). Xiong and his colleagues consistently
mTOR signaling by miR-99a can impede the cell cycle of BC cells [246]. reported that miR-30a-5p represses β-catenin downstream targets like
Other studies have also confirmed the inhibitory effect of miR-15 and cyclin B1, cyclin D1, and c-Myc in BC cells [260]. The miR-384 is
miR-16 in BC [249]. another TS that inhibits Activin A receptor type 1 (ACVR1), resulting in

Fig. 4. Role of p53 and PTEN/AKT/PI3K and Wnt/β-catenin signaling pathway in BC. A. Oncogenic miRNA-93 targets and obstructs the PTEN gene-promoting BC.
miR-99, miR-204, and miR-125b suppress mTOR expression, thus inhibiting BC proliferation and reducing drug resistance B. The canonical Wnt/-catenin pathway is
crucial for tumor growth. By interacting with the Wnt ligand, glycogen synthase kinase 3 beta (GSK-3β) is inhibited, and β-catenin ubiquitination is stopped.
β-Catenin builds in the cytoplasm and transfers to the nucleus, where it forms complexes with transcription factors like TCF/LEF to regulate the transcription of
downstream genes involved in cellular differentiation and proliferation. Without Wnt ligands, GSK-3β phosphorylates β-catenin by building a destruction complex
with Axin, CKI, APC, and GSK-3β, leading to β-catenin degradation via the ubiquitin system (Ub). Some miRNAs target activated Wnt/β-catenin signaling to limit BC
advancement, whereas others target inactive signaling to stimulate BC progression.

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Table 4 tumorigenic and anti-metastatic effects in primary BC cells [271]

miR-Related Mechanisms in BC. (Table 4 and Fig. 5A).
Mechanisms miRNAs Targets Alteration Ref.
4.4. MAPK signaling pathway
PI3K/AKT/mTOR miR-122 IGF1R, PI3CG ↓↓↓ [245]
signaling miR-99 mTOR [246]
miR-204 [247] Atypical RAS- MAPK signaling pathway stimulation is a predominant
miR-125b [248] oncogenic incident in various tumors, including BC [272]. Increased
miR-99a [246] expression of miR-133a repressed cell proliferation, metastasis, and
miR-96 mTOR/AKT ↑↑↑ [250]
miR-221 [252]
invasiveness in BC cell lines and tissues that object to epithelial growth
miR-93 PTEN [251] factor receptor (EGFR) [273].
Wnt/β catenin miR-1229 GSK-3 β, APC ↑↑↑ [254] SPRED1 and RASA1 act as negative controllers of the RAS-MAPK
signaling miR-1301 ICAT [255] signaling pathway. It has been verified that miR-206 and miR-21 sup­
miR-125b APC [256]
pressed the expression of both RASA1 and SPRED1 by targeting their
miR-3646 GSK-3 β [257]
miR-29a GSK-3 β, [258] mRNA 3′ -UTRs in triple-negative BC [274]. Another target in the MAPK
PTEN pathway, NRAS, was directly down-regulated by miR-148b in violent
miR-374a WIF1 [143] breast tumors and was verified to be involved in tumor cell invasion and
miR-135 GSK-3 β ↓↓↓ [259] chemotherapy resistance, suggesting miR-148b as a promising
miR-30a- Cyclins, c- [260]
5p Myc
biomarker for aggressive BC [275].
miR-384 ACVR1 [261] In BC cell lines, miR-543 was approved to suppress ERK2 activity,
miR-140- Wnt1 [262] preventing tumor growth [276]. Additionally, miR-550a-3p negatively
5p controls ERK1/ERK2 and downregulates the ERK/RSK flows to decrease
miR-100 SFPRs [263,264]
tumor development, migration, and invasiveness of cells [277] (Table 4
miR-27a
JAK/STAT signaling miR-155 SOCS1 ↑↑↑ [267] and Fig. 5B). The TS properties of Let-7a in BC cells are exerted via the
miR-30c SOCS3 [268] regulation of KRas/NF-κB and KRas/MEK/ERK pathways [278].
miR-29b STAT1 ↓↓↓ [279]
miR-146b STAT3 ↓↓↓ [270] 5. The clinical applications of miRNAs in BC
miR-7 [271]
MAPK signaling miR-133a EGFR ↓↓↓ [273]
pathway miR-206 RASA1, ↑↑↑ [274] 5.1. MicroRNAs as diagnostic biomarkers for BC
miR-21 SPRED1
miR-148b NRAS [275] Early detection of BC offers successful treatment and improvement of
miR-543 ERK2 [276]
↓↓↓
the prognosis. So consequent studies are growing up for the identifica­
miR-550a- ERK1/ERK2 [277]
3p tion of unique miRNA patterns that could be useful as diagnostic and
prognostic biomarkers for BC.
Emerging studies show that miR-21 could be measured stably and
repression of Wnt/β-catenin [261]. In harmony, miR-140-5p is another easily in tumor tissues [280,281], serum [282,283], and plasma [284]
Wnt inhibitory miRNA that targets Wnt1 and is down-regulated in BC and can distinguish between patients with BC and healthy women
stem cells [262]. Moreover, Wnt frizzled receptors and their related (Table 5). Mar-Aguilar and his team showed that the sensitivity and
proteins may be promising BC therapy targets. Noteworthy, miR-100 specificity of miR-21 to differentiate BC from normal tissue were 75 and
and miR-27a inhibit secreted frizzled receptor protein (SFRPs), 60 %, respectively, while combining the expression of miR-21 and miR-
restricting tumor proliferation and invasion [263,264] (Table 4). 191 increased the sensitivity to 92 % and specificity to 100 %, sug­
gesting that miRNA could be used as a novel diagnostic tool for differ­
4.3. JAK/STAT signaling pathway entiation between BC from normal tissue [281]. A recent study carried
out by Li et al. on the serum of 49 patients with BC and a similar number
The JAK/STAT pathway influences growth and stem cell mainte­ of healthy subjects showed that serum levels of miR-9-5p and miR-148a-
nance. Additionally, this pathway plays a crucial role in orchestrating 3p were correlated positively with the presence of BC and may be used
the immune system, particularly cytokine receptors [265,266]. Active as non-invasive biological markers of high sensitivity and specificity for
JAKs activate STAT proteins, which form dimers and translocate to the the clinical diagnosis of BC [285] (Table 5). A meta-analysis study
nucleus when phosphorylated. These dimers control proliferation, dif­ showed that miR-34a is suggested to be a promising non-invasive
ferentiation, and apoptosis-like SOCS gene transcription [265,266]. biomarker in different diagnosing BC [286]. A set of miRNAs panel
There are eight members of the SOCS1, SOCS2, SOCS3, SOCS4, SOCS5, including let-7b-5p, miR-106a-5p, miR-19a-3p, miR-19b-3p, miR-20a-
SOCS6, SOCS7, and cytokine-inducible SH2 domain protein that play 5p, miR-223-3p, miR-25-3p, miR-425-5p, miR-451a, miR-92a-3p, miR-
pivotal roles in immune regulation [265,266]. 93-5p, and miR-16-5p was recently identified as potential none inva­
The miRNA-155 is reported to promote BC by targeting SOCS1 as a sive marker in serum for diagnosis of BC [287]. The expression level of
TS gene [267]. In a study, decreased miRNA-30c expression caused an miR-126-5p in blood samples is a good marker for diagnosing TNBC
increase in SOCS3 levels, a decrease in STAT3 phosphorylation, and patients [288].
consequently suppressed expression of downstream genes, leading to
increased BC cell apoptosis [268]. Decreased miRNA-29b expression 5.2. Differentiation between BC subtypes
promoted metastatic BC by triggering the STAT1 pathway promoting
breast cancer cell growth, drug resistance, migration, and invasion Breast cancer is classified into six major subtypes that differ from
[269]. each other in aggressiveness; these subtypes are Luminal A, Luminal B,
Interestingly, higher methylation of the TS miRNA-146b promoter HER2 positive (HER2+), normal-like, TNBC (or basal-like), and claudin-
was identified in primary BC, which had a negative feedback loop with low [289,290]. The luminal subtypes are mainly HR+ and generally are
activation of nuclear factor kappa B (NF-κB) and STAT3 with an increase PR+, ER+, and HER2-negative tumors [291]. Luminal B is associated
in the migration and invasion of BC cells [270]. Furtherly, miRNA-7 was with a high recurrence risk [292]. TNBC losses ER, PR, and HER2
reported as an adverse controller of interleukin-6 (IL-6) by binding to expression exhibits a bad prognosis and is currently not subject to bio­
the 3′ -UTR of its upstream intermediary. Thus, it seems to have anti- logical treatment [293]. Normal-like subtype expresses a similar genetic

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Fig. 5. Role of JAK/STAT and MAPK signaling

pathway in BC. A. JAK/STAT signaling pathways are
activated and are negatively regulated. The miRNA-
155 and miRNA-30c are reported to promote BC by
targeting TSs SOCS1 and SOCS3, respectively.
miRNA-146b and miRNA-7 suppress JAK/STAT
signaling pathway by targeting STAT3. B. MAPK
signaling pathway showing the target genes of miR­
NAs. The miR-206 and miR-21 promote BC by tar­
geting TSs RASA1 and SPRED1. The miR-133a
suppresses proliferation and invasiveness in BC cell
lines and tissues by targeting the epithelial growth
factor receptor (EGFR). The miR-543 and miR-550a-
3p were approved to prevent tumor growth by tar­
geting ERK2 and ERK1/ERK2 activity, respectively.

pattern to normal breast tissue [292]. However, the claudin-low subtype factors of patients were studied. Results showed that miR-221 expres­
(aggressive) is characterized by TN with an EMT state, cancer stem cell- sion was significantly higher in cancerous tissues than in normal tissues,
like markers, and immune response [290]. and high miR-221 expression was positively correlated with advanced
Distinct subtypes of BC exhibit different molecular miRNA signa­ clinical stages. Furthermore, patients with higher miR-221 expression
tures. Depending on this basis, several studies were carried out to had worse 5-year free survival [300] (Table 5).
identify subtype-specific miRNAs that could be used to differentiate A study performed by Han et al. on 197 cases of invasive BC showed
between BC subtypes. Regarding the association of miRNAs with BC that the expression of miR-222 was evaluated by real-time PCR. High
subtypes, let-7f, let-7c, and miR-10a were found to be associated with expression of miR-222 was associated with high histologic grade, high
the Luminal A subtype; miR-142-3p and miR-150 were associated with tumor stage, EMT, and poor clinical outcome in hormone receptor-
the HER2+ subtype; while miR-93, miR-18a, miR-135b, and miR-155 positive BC [301]. The miR-210 expression was correlated to poor
were correlated with TNBC [294] (Table 5). Lowery and his col­ clinical outcomes in ER+ BC patients and identified as a strong prog­
leagues demonstrated that miR-342 was specifically up-regulated in nostic biomarker [302]. Serum miR-103a-3p levels were upregulated in
HER2+ Luminal B cases [295]. A recent study performed by Søkilde BC patients more than in healthy women. Its expression level was also
et al. used small RNA sequencing for 186 tumor samples subdivided associated with advanced clinicopathological features, including
according to HER2 and ER expression into ER+/HER+, ER+/HER− , metastasis, advanced TNM stage, and worse survival outcomes in pa­
ER− /HER+, and ER− /HER− . They stated that miRNA expression levels tients with BC. Serum level of miR-103a-3p could be used as a good
could facilitate the discrimination of specific BC subtypes, and they biomarker for distinguishing patients with metastatic BC from those
revealed that miR-99a/let-7c/miR-125b could differentiate Luminal A without metastasis and could be a potential noninvasive diagnostic and
from the B subgroup while miR-4728 specifically can identify HER2- prognostic biomarker for BC [303] (Table 5).
enriched tumors [296]. Furthermore, Tang et al. observed that miR-
193a-3p downregulation was associated with HER2+ BC cells and tis­
sues [297]. Beyond the dysregulation of miRNAs in various subtypes of 5.4. Detection of metastasis
BC tissues, various studies were performed to analyze the differential
expression of miRNAs in circulation as a noninvasive tool for predicting The miRNAs have a critical role as biomarkers for detecting metas­
the subtype. For differentiation between Luminal BC patients and tasis in BC. The first miRNA shown to be highly expressed in metastatic
healthy controls, McDermott et al. investigated the blood miRNAs of 54 BC was miR-10b which was detected in tissue [304] and serum [305]
patients with Luminal-A BC and 56 healthy people. They showed that samples. Growing studies were carried out to identify miRNAs as a
miR-29a, miR-181a, and miR-652 expression were decreased in patients biomarker for metastatic BC; miR-200c and miR-141 were high upre­
who may serve as specific Luminal A tumor subtype detectors [298]. gulated in plasma of patients with metastatic BC than in plasma from
Another study carried out by Godfrey et al. revealed that the differential those with localized BC exhibiting a potential role in the early detection
expression of serum levels of 7 miRNAs (miR-183, miR-378, miR-29a, of BC metastases [306] (Table 5).
miR-93, miR-660, miR-4281, and miR-4283) was identified in HER2+ A combination of serum miR-629-3p and miR-4710 was beneficial in
versus HER2− BC women [299] (Table 5). diagnosing axillary lymph node metastasis in patients with BC and
considered a less invasive biomarker than Sentinel lymph node biopsy
[307]. Furthermore, a study conducted by McAnena et al. to explore
5.3. microRNAs as prognostic markers circulating miRNAs that can detect metastasis showed that miR-331 was
significantly over-expressed and miR-195 was significantly under-
Besides the usefulness of miRNAs in aiding the diagnosis of BC, they expressed in BC patients with metastatic disease compared to those
also have a potential prognostic role. The expression of miR-221 in 76 with local disease or healthy; both miRNAs can detect the metastatic
tissue samples of BC and its correlations with the clinical-pathological disease while the detection power increased when both miRNAs were

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Table 5 the expression of both miRNAs before neoadjuvant chemotherapy could

Clinical applications of miRNAs in BC. be used to predict the responsiveness [310] (Table 5).
Clinical application miRNAs Specimen Ref. Profiling of Circulating exosomal miRNAs before and 14 days after
the first cycle of NACT (Adriamycin + Cyclophosphamide) for invasive
Diagnosis of BC miR-12 Tissue [280,281]
Serum [282,283] ductal carcinoma in 20 BC patients revealed that exo-miR-423, exo-miR-
plasma [284] 30b, and exo-miR-328 predicted PCR in all samples while exo-miR-127
miR-9-5p, Serum [285] correlated with PCR in TNBC [311]. Circulating miR-21, miR-195, and
miR-148a-3p miR-145 were demonstrated as biomarkers for predicting NACT
let-7b-5p, miR-19b-3p, miR- Serum [287]
19a-3p, miR-106a-5p, miR-20a-
response in BC women [312]. Li et al. suggested that serum miR-451a,
5p, miR-425-5p, miR-25-3p, miR-16-5p, miR-17-3p, and miR-940 signatures can distinguish be­
miR-223-3p, miR-451a, miR- tween HER2+ metastatic BC patients who are responders to trastuzu­
16-5p, miR-93-5p, and miR- mab from the non-responders [313]. miR-34a offers a prediction tool for
92a-3p
PCR in TNBC patients undergoing platinum-based NACT [288]
miR-126-5p Blood [288]
Differentiation let-7c, let-7f and miR-10a Tissue [294] (Table 5).
between BC miR-142-3p, miR-150 (Luminal
subtypes A subtype) 5.6. Prediction of recurrence
miR-93, miR-18a, miR-135b,
miR-155 (HER2+ subtype)
miR-93, miR-18a, miR-135b
Almost 30 % of BC patients tend to develop local or distant recur­
and miR-155 (TNBC) rence [314]. Breast cancer recurrence results from malignant cells that
miR-342 (Luminal B subtype) Tissue [295] are not removed by surgical resection or systemic therapy and then start
miR-99a/let-7c/miR-125b Tissue [296] to increase and form local or distant metastases [315]. The development
(luminal A from luminal B)
of novel biomarkers for early prediction of patients at high risk of
miR-4728 (HER2+)
miR-193a-3p (HER2+) Tissue [297] recurrence is an urge to improve the management of patients with BC.
Cell lines Likely, miRNAs are expressed differentially between relapsed and non-
miR-29a, miR-181a, miR-652 Blood [298] relapsed patients and can predict recurrence before clinical detection.
(luminal A from healthy For example, miR-21, miR-23b, and miR-200c were highly expressed,
control)
miR-183, miR-93, miR-29a, Serum [299]
while miR-190 was lower expressed in relapsed patients compared to
miR-660, miR-378, miR-4281, non-relapsed and these miRNAs can discriminate relapsed from non-
miR-4283 (HER2+ from relapsed patients [316] (Table 5).
HER2− ) Masuda et al. found that overexpression of circulating pre-miR-488
Prognosis miR-221 Tissue [300]
was observed in surgically treated patients with recurrence and identi­
miR-222 [301]
miR-210 [302] fied that pre-miR-488 expression could be a novel biomarker to predict
miR-103a-3p Serum [303] recurrence in BC patients [317]. Kim and his team studied the profile of
Detection of miR-10b Tissue [304] miRNAs to identify those associated with distant recurrence during
metastasis Serum [305] tamoxifen treatment. They observed that miR-134, miR-125b-5P,
miR-200c, miR-141 Plasma [306]
miR-629-3p/miR-4710 Serum [307]
miRNANA-30a, miR-10a-5p, and miR-222 were up-regulated in cases
miR-195, miR-331 Plasma [308] with distant recurrence within 5 years after surgery and during tamox­
exosomal miR-21 and miR-105 Serum [309] ifen treatment, such as miRNAs can predict recurrence [318].
Prediction of miR-7, miR-340 Tissue [310]
response to Exo-miR-423, exo-miR-127, Plasma [311]
6. Therapeutic interventions of miRNAs in BC
treatment exo-miR-328, exo-miR-30b
miR-21, miR-195 and miR-145 Blood [312]
miR-451a, miR-940, miR-17- Serum [313] A nucleic acid-based therapeutic strategy is one in which the nucleic
3p, and miR-16-5p acid is chemically modified and used to restore the normal activity of
miR-34a Blood [288] miRNAs. The main nucleic acid-based therapies are miRNA mimic
Prediction of miR-21, miR-190, miR-200c, Plasma [316]
recurrence miR-23b
therapy, anti-miRNA therapy, or combined with radiotherapy [319].
pre-miR-488 Serum [317].
miR-134, miR-10a, miR-30a, Tissue [318] 6.1. miRNA mimic therapy
miR-125b-5P -5p and miR-222
The miRNA substitution provides a novel approach to investigating
the therapeutic potential of tumor suppressors. The miRNAs provide a
measured in a combination [308]. Expression levels of exosomal miR-21
novel potential since, unlike proteins, they are much smaller, require
and miR-105 were higher in metastatic compared to non-metastatic
only entry into the cytoplasm of target cells to be active, and may be
patients and healthy women [309] (Table 5).
given systemically utilizing the same modes and technologies as siRNAs.
As a result, the delivery barrier for miRNA mimics seems less difficult
5.5. Prediction of response to treatment than for protein-coding DNA [320].
According to Liang et al., study miR-302s are downregulated in
Neoadjuvant chemotherapy (NACT) reduces tumor size in locally radioresistant breast cancer cells relative to their parental cells, with an
advanced BC before surgical resection. The response to the treatment is elevation of AKT1 and RAD52 expression levels. The miR-302 replace­
evaluated by achieving a pathologic complete response (PCR). Unluck­ ment mimic only replenishes depleted endogenous miRNAs by targeting
ily, there is no clinically validated method for predicting the respon­ the same genes as the naturally existing miRNA, avoiding “off-target”
siveness of BC patients to NACT. Hence, identifying a new biomarker for effects and toxicity. Indeed, the in vivo results revealed no evidence of an
predicting the response is necessary to determine the proper therapy for off-target impact. As a result, the study suggests that using miR-302
optimum BC management. The expression of 10 miRNAs was deter­ replacement treatment as a radiosensitizer for BC may be safe [321].
mined by real-time PCR from biopsy before therapy and invasive tumor The ABC transporter family member MRP-1 was targeted by miR-
after anthracycline/taxane-based NACT. The miR-7 overexpression and 326, which was downregulated in BC tissues. The miR-326 oligonucle­
miR-340 down expression in pre-therapeutic biopsies predicted PCR. So otide mimics were added to BC cell lines to improve doxorubicin

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susceptibility [322]. transformation from the M1 to M2 phenotype in macrophages promotes

Tail vein injections of LM2-4142 or MDA-MB-231 cells were also tumor growth. The miR-19a-3p controls the TAM phenotype by target­
used to study the effect of miR-145 on metastasis. Either the miR-145- ing the Fra-1 gene and other genes in its downstream signaling pathway.
expressing construct or a control construct was used to infect cells. An inverse association between Fra-1 and miR-19a-3p expression was
There were 72 % fewer nodules in animals injected with miR-145- discovered, showing that the 3′ UTR of Fra-1 may be a miR-19a-3p
expressing cells. These have confirmed the miR-145's function as a target. RAW264.7 cells were transfected with a miR-19a-3p mimic to
metastasis suppressor in vivo data. The miR-145 has also been proven to confirm this. The miR-19a-3p mimic drastically reduced Fra-1 expres­
target MUC1, and MUC1 has been shown to enhance invasiveness [323]. sion. Fra-1 expression and the polarization of macrophages have been
In TNBC cells, the in vitro tests show that miR-34a-NPs can influence reduced by injecting ago miR-19a-3p in vivo, which could help prevent
Notch signaling and downstream miR-34a targets. Establishing co- BC metastasis and prognosis, as shown in Table 6 [326].
delivery of miR-34a and Notch1 antibodies via NPs is a promising The miR-542-3p is a strong TS molecule targeting the TS p53 and the
technique for delivering these antibodies, causing senescence and apoptotic inhibitor survivin. Hyaluronic acid-coated polyethyleneimine-
reducing cell proliferation and migration. TNBC is being treated inno­ poly (d,L-lactide-co-glycolide) nanoparticles were designed for co-
vatively [324] (Table 6). Also, miR-34a Regulates AXL expression and delivery of doxorubicin and miR-542-3p in triple-negative BC treat­
reduces cell invasion and vasculogenic mimicry formation in MDA-MB- ment. Intracellular miR-542-3p replacement therapy increased
231 BC cells [325] (Table 6). apoptosis in TNBC cells by activating p53 and reducing survivin pro­
Tumor-associated macrophages migrate to the tumor site, enhancing duction in vitro [327].
angiogenesis, tumor cell motility, invasion, and metastasis. The The miR-4306 is controlled by HER2− , ER− , and PR, and its
downregulation in TNBC results from their loss. The miR-4306 expres­
sion is significantly associated with lymph node metastases and poor
Table 6
Some miRNAs replacement therapy. survival in patients with TNBC. In vitro, upregulation of miR-4306
significantly inhibits TNBC cell proliferation, angiogenesis, invasion,
miRNA Formula In In vitro Action Ref.
migration, and lymphangiogenesis. In vivo, overexpression of miR-4306
vivo
reduces TNBC development, lymph node metastasis, and lung metastasis
miR- Nanoparticles MDA-MB-231 Reduce TNBC [324]
–
[328].
34-a TNBC cells cell migration
and The miR-145 is a downregulated TS miRNA in cancer and may be
proliferation used therapeutically in various malignancies, including BC. The miR-
miR- miR-34-a – MDA-MB-231 Reduces cell [325] 145 plasmid was transfected into MCF-7 cells using chitosan polyplex
34-a mimic TNBC cells migration, nanoparticles, which inhibit the growth of MCF-7 cells efficiently [329]
transfection invasion, and
(Table 6).
vasculogenic
mimicry The multilayered NPs containing the metastasis suppressor miR-708
formation (miR-708-NP) localize to orthotopic primary TNBC and successfully
miR- miR-19a-3p Mice RAW264.7 Suppression of [326] transfer the miR-708 cargo to the lungs inhibiting lung metastasis. De­
19a- mimic macrophages the Fra-1 gene
signers found a group of low miR-708 cancer cells with tumor-starting
3p transfection leads to
inhibition of the
features, improved metastatic potential, and strong sensitivity to miR-
invasion and 708 therapy using a SOX2/OCT4 promoter-reporter. The miRNA708-
progression of NP inhibited metastasis in vivo by specifically targeting SOX2/OCT4-
breast tumors. mCherry+ miR-708 low tumor cells. Together, these results provide a
miR- Nanoparticles MDA-MB-231 Promoted TNBC [327]
mechanism-based antimetastatic treatment strategy for TNBC, with a
–
542- TNBC cells/ cell apoptosis
3p MCF-7 cells via inhibiting strong potential for clinical development of miR-708 replacement
survivin therapy for high-risk TNBC patients [330] (Table 6).
expression and
activating p53.
6.2. Anti-miRNA therapy
miR- Cholesterol- Mice R-75-1, MCF-7, Inactivates the [328]
4306 conjugated T47D, SK-BR- signaling
miR-4306 3, HCC1937, pathways Two ways are employed to deactivate particular oncomiRs in the
mimic. MDA-MB-468, mediated by instance of upregulated oncomiRs. The first one involves the expression
CAL-51 SIX1/Cdc42/ of miRNA sponges through expression vectors. The miRNA sponges are
VEGFA.
Suppresses
composed of many copies of a given miRNA binding site connected by a
TNBC cell short spacer [331], which may diminish the quantity of miRNA avail­
proliferation able to bind to and inhibit target mRNAs. Additionally, it is feasible to
and invasion suppress a whole family of miRNAs by utilizing a common seed
and abrogates
sequence. Additionally, several miRNA sponges demonstrated long-term
angiogenesis
miR- Nanoparticles – MCF-7 Suppressing [329] suppression in vivo. Apart from synthetic miRNA sponges, naturally
145 proliferation occurring miRNA sponges have been identified as circular RNA pro­
miR- Nanoparticles Mice MDA-MB-231 miR-708 [330] duced in the cell by back splicing (an alternative RNA splicing) [332].
708 targeted AntagomiRs are miRNA antagonists that act by binding to and
endoplasmic
reticulum
inhibiting oncomiRs. These nucleic acid antagonists are one recognized
membrane method of inhibiting oncomiRs, which may be an effective cancer
protein treatment method [333]. AntagomiRs are chemically designed antisense
Neurontin to oligonucleotides that include 2-O-methylated ribose residues, 3-conju­
decrease
gated cholesterol residues, and partial replacement of phosphodiester
intracellular
calcium levels, bonds through phosphorothioate linkages, with one of the non-bridging
resulting in oxygens replaced by Sulphur [319].
reduced Anti-miRNAs may be delivered locally or systemically, depending on
activation of the organ or tissue in question and the toxicity of these agents in non-
ERK and FAK
target organs. Furthermore, these oligonucleotides may be delivered

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by virus, lipid, or nanoparticle vectors [331]. encapsulate estrogen receptor (ER)- α targeted short interface RNAs
Lipid vectors are composed of a lipid bilayer that facilitates miRNA (siRNA). However, they may have some drawbacks as low yield in
distribution into cells and protects them from destruction by nucleases. PIBCA encapsulation and diminished releases in PEG− PLGA. On the
Cationic liposomes had considerable effects due to their positively other hand, siRNA loaded in PEG− PCL/MA nanocapsule exhibited a
charged membrane assisting in their absorption by the negatively high release level and therapeutic efficacy [354].
charged cellular membrane [334]. Numerous changes have been made Furthermore, the newly synthesized generation 4 of methotrexate-
to improve their delivery effectiveness, such as the coupling of poly­ modified polyamidoamine dendrimer has been reported to be loaded by
ethylene glycol to cationic lipids [335]. Zhang et al. have made an siRNA. This complex has enhanced apoptosis by its suppressive action
intriguing alteration, constructing miR-10b antagonists and paclitaxel on HMGA2 in human BC [355].
using a PH-responsive liposome modified with the antimicrobial peptide
[D]-H6L9 (D-Lip) [336]. This innovative method demonstrated a delay 7. Limitations and future prospective
in tumor development and reduced lung metastasis in mouse BC models.
They are commonly utilized for miRNA delivery in vivo. The key objective in breast oncology is to improve the diagnostic,
Cava et al. employed atelocollagen to deliver antisense miR-429 to a prognostic, and predictive tools to optimize the management and
HER2+ mouse model. The findings demonstrated a considerable treatment of BC. To this date, various molecular analyses can be applied
reduction in tumor development, indicating that anti-sense miR-429 was to different specimens to help identify well-established markers to guide
successfully delivered by atelocollagen [337]. the diagnosis, molecular subtype classification, prognosis, and optimum
CircRNA-7 has been controlled by miR-671 and serves in the mouse treatment. miRNAs exhibit the advantage of not being detected only in a
brain as a miRNA sponge for miR-7 [338]. The alternative strategy is to tissue biopsy. They can be released into liquid biopsy samples such as
introduce chemically produced anti-sense oligonucleotides with a length blood, milk, urine, and other bodily fluids. Hence, circulating miRNAs
of 17 to 22 nucleotides that can successfully bind to a particular miRNA have the potential to be non-invasive biomarkers for diagnosis, prog­
and prevent its binding to the 3′ UTR of target mRNAs. These anti- nosis, molecular subtyping, monitoring therapy response, prediction of
miRNA oligonucleotides, often known as antisense, are synthesized in relapse, and developing new therapeutic methods in BC management.
vitro [331]. In one investigation, an antisense miR-21 oligonucleotide Studying the circulating miRNAs may reveal molecular aspects
was shown to be capable of restoring trastuzumab sensitivity in BC regarding BC's causes, therapeutic resistance, and recurrence. Genomics,
[339]. transcriptomics, proteomics, and metabolomics can be integrated to
build up multidimensional data. These data can be combined with
6.3. miRNAs combined with radiotherapy various detection techniques and powerful statistical analysis to identify
novel circulating miRNAs in the liquid biopsy that are of clinical validity
miRNAs can effectively influence radiation sensitivity by regulating and utility.
the expression of genes involved in the biological process related to
response to IR, such as essential proteins for detecting DNA damage and 8. Conclusion
activating the cell death signaling cascade [340]. So far, the association
of certain miRNAs, such as miR-483, miR-34a, miR-199, miR-208, miR- In a nutshell, miRNAs regulate BC stemness, initiation, progression,
105/-16, and Lin28-let7 [341–346] with cellular resistance and sensi­ and therapy response through controlling many biological processes,
tivity to radiation has been identified. These microRNAs are responsible including BCSCs differentiation and renewal, cell cycle maintenance,
for regulating the expression of genes that are effective in enhancing cell apoptosis, angiogenesis, metastasis, EMT, and resistance to major
protection against radiation, such as the RAD52 and MDM4 DNA repair treatment regimens. On the molecular side, miRNAs manage the BC
families [347], TGF-β [348], and WNT [349] in the apoptotic signaling biological processes via modulating many signaling pathways. Hence,
cascade. let-7d significantly inhibited the malignant behaviors of TNBC profiling and understanding miRNAs is so critical to be utilized in BC
cells in vitro and suppressed the self-renewal abilities of CSCs. Further­ diagnosis, subtyping, prognosis, and even prediction of recurrence and
more, in HS587-T and MM-231 cells, it was identified that let-7 func­ therapy response. Moreover, many tumor suppressor miRNAs and anti-
tioned by inhibiting the cyclin D1/Akt1/Wnt1 pathway and sensitized oncomiRs have been developed as therapeutic interventions alone or
TNBC to radiation therapy-induced renewal repression [350]. combined with other traditional BC therapy.
Additionally, the production of genes or autophagy makes cancer
cells resistant to traditional therapeutic drugs. Targeting regulatory Funding
pathways hence provides targeted therapy and lowers drug resistance.
PTT can cause apoptosis in tumor localization and is a secure, non- This research did not receive any specific grant from funding
invasive method [351]. agencies in the public, commercial, or not-for-profit sectors.

6.4. New miRNA delivery systems applied in the treatment of BC CRediT authorship contribution statement

As we discussed above, miRNA mimics or inhibitors have been Ahmed Ismail: Conceptualization, Methodology, Supervision,
applied in the treatment of BC. These agents require delivery systems to Writing – original draft, Writing – review & editing. Hesham A. El-
be applied to the target tissues. Nanocapsules are applied to deliver Mahdy: Investigation, Writing – original draft, Data curation, Method­
some miRNAs in the treatment of BC [352]. Nanocapsules based on ology. Ahmed I. Abulsoud: Conceptualization, Supervision, Visualiza­
hyaluronic acid/protamine sulfate interpolyelectrolyte complexes (HP/ tion, Writing – original draft, Writing – review & editing. Al-Aliaa M.
IPECs) have been established for encapsulation and intracellular transfer Sallam: Conceptualization, Writing – original draft, Formal analysis,
of miR-34a (BC tumor suppressor). HP/IPECs encapsulated miR-34a has Supervision. Mahmoud Gomaa Eldeib: Conceptualization, Writing –
been reported to be efficiently delivered to BC cells or tissues in vitro and original draft, Visualization. Elsayed G.E. Elsakka: Visualization,
in vivo. HP/IPECs encapsulated miR-34a targeted Notch-1-signaling Investigation, Writing – original draft. Mohamed Bakr Zaki: Supervi­
pathway and CD44, leading to proliferation, migration suppression, sion, Conceptualization, Writing – original draft. Ahmed S. Doghish:
and induction of apoptosis [353]. Another types of nanocapsules used in Conceptualization, Writing – original draft, Resources, Supervision,
BC include poly(isobutyl cyanoacrylate) (PIBCA), poly(ethylene)glycol- Writing – review & editing.
poly(d,L-lactide-co-glycolide) (PEG− PLGA) and PEG-ε-caprolactone-
malic acid (PEG− PCL/MA). Some nanocapsules are developed to

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A. Ismail et al. International Journal of Biological Macromolecules 224 (2023) 1541–1565

Declaration of competing interest [24] A.S. Doghish, A.M. Elsisi, A.I. Amin, A.I. Abulsoud, Circulating miR-148a-5p and
miR-21-5p as novel diagnostic biomarkers in adult egyptian male patients with
metabolic syndrome, Can. J. Diabetes 45 (7) (2021) 614–618, https://doi.org/
The authors declare that they have no known competing financial 10.1016/j.jcjd.2020.12.005.
interests or personal relationships that could have appeared to influence [25] M.Bakr Zaki, A.I. Abulsoud, A.M. Elsisi, A.S. Doghish, O.A.E. Mansour, A.I. Amin,
the work reported in this paper. M.A. Elrebehy, M.Y. Mohamed, M.A. Goda, Potential role of circulating
microRNAs (486-5p, 497, 509-5p and 605) in metabolic syndrome Egyptian male
patients, Diabetes Metab. Syndr. Obes. 12 (2019) 601–611, https://doi.org/
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