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Critical Reviews in Oncology / Hematology 182 (2023) 103901
Available online 28 December 2022
1040-8428/© 2022 Elsevier B.V. All rights reserved.
Inhibition of WNT signaling by conjugated microRNA nano-carriers: A new
therapeutic approach for treating triple-negative breast cancer a
perspective review
Manosi Banerjee, V. Devi Rajeswari
*
Department of Biomedical Sciences, School of Bioscience and Technology, Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India
ARTICLE INFO
Keywords:
Triple-negative breast cancer
MicroRNA
Wnt signaling
EMT
Nanocarriers, Anti-drug resistant
Chemotherapy
ABSTRACT
Triple-Negative Breast Cancer is the most aggressive form and accounts the 15%−25% of all breast cancer.
Receptors are absent in triple-negative breast cancer, which makes them unresponsive to the current hormonal
therapies. The patients with TNBC are left with the option of cytotoxic chemotherapy. The Wnt pathways are
connected to cancer, and when activated, they result in mammary hyperplasia and tumors. The tumor suppressor
microRNAs can block tumor cell proliferation, invasion, and migration, lead to cancer cell death, and are also
known to down-regulate the WNT signaling. Nanoparticles with microRNA have been seen to be more effective
when compared with their single release. In this review, we have tried to understand how Wnt signaling plays a
crucial role in TNBC, EMT, metastasis, anti-drug resistance, and regulation of Wnt by microRNA. The role of
nano-carriers in delivering micro-RNA. The clinical biomarkers, including the present state-of-the-art, involve
novel pathways of Wnt.
Abbreviations: TNBC, Triple-negative breast cancer; miRNA, microRNA; ER, Estragon; PR, Progesterone; HER2, Human epidermal growth factor receptor 2; RNA,
Ribonucleic acid; DNA, deoxyribonucleic acid; BLIA subtypes, Basal Like immune Activated; LAR subtype, Luminal Androgen Receptor; BLIS, Basal like immune
suppressed; MSL, Mesenchymal stem-like; M, Mesenchymal; ABC, ATP-binding cassette; Akt, RAC-alpha serine/threonine- protein kinase; BCSC, Breast cancer stem
cell; ER, The estrogen receptor; FZD, Frizzled; HIF-1a, Hypoxia inducing factor 1a; RP, Multidrug-resistant protein; MUC1, Mucin 1; PARP, Poly ADP-ribose poly-
merase; PI3K, Phosphatidylinositol 3-kinase; PIK3CA, Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PR, Progesterone receptor; P-GP, P-
glycoprotein; siRNA, Small interfering RNA; TCF, T cell factor; TGFBR, Transforming growth factor receptor; MDR, Multi drug Resistant; TP53, Tumor protein P 53;
PIK3CA, Phosphatidylynositol4,5-bisphosphate 3-kinase catalytic subunit A; PTEN, Phosphatase and Tensin homolog; EGFR, Epidermal Growth Factor receptor;
MCL1, Myeloid leukemia cells protein 1; PARP1, (Poly (ADP-ribose)polymerase); VEGFR, Vascular Endothelial Growth factor; ALDH1, Aldehyde dehydrogenase 1;
STAT3, Signal transducer and activator of transcription 3; IL6/IL8, Interleukin 6/8; STAT1/NOTCH3, Signal transducer and activator of Transcription 1 Neurogenic
locus notch homolog protein 3; NSCLC, Non-small cell lung cancer; TWIST/SNAIL/FOXC2, Zinc Finger protein SNAI/Forkhead Box Protein C2; ROS:Proto-Oncogene,
Receptor tyrosine kinase; ZEB1/CHK1, Zinc Finger E -box- binding homeobox 1/ Checkpoint kinase 1; ERK, Extracellular signal-regulated kinase; CDK4, Cyclin-
dependent kinase 4; GAS6, Growth Arrest -Specic 6; IGF-1R, Insulin-like growth factor −1 Receptor; BMP4/BMP7, Bone morphogenetic protein 4 and 7; KRAS, Ki-
ras2 kirsten rat sarcoma viral oncogene homolog; TGF-2, Tumor growth factor 2; ATG4, Autophagy-regulating protease 4; PI3K, Phosphoinositide 3 –kinases; ABCG2,
ABC-super family G member 2; EGF/RAS/ERK, Epidermal growth factor receptor/Rat Sarcoma protein/Extracellular regulated kinase; RAF/MEK/ERK, Rapidly
accelerated bro sarcoma/Mitogen-activated protein kinase/Extracellular-signal regulated kinase; TCF/LEF, T-cell factor/ lymphoid enhancer factor; SFRP2,
Secreted Frizzled-related protein 2; DKK2, Dickkopf Wnt signaling pathway inhibitor 2; ADAM10, Glycosylated type 1 membrane protein; HnRNPA1, Heterogenous
nuclear ribonucleoprotein A1; SLUG, SNAI2 instructor gen; GSK3, Glycogen synthase kinase 3; IKB, Inhibitor of nuclear factor kappa B; NF- κB, Nuclear factor kappa
B; PTK, Protein tyrosine kinase; β-TrCP, β-Transducin repeat-containing protein; RNF43, Ring nger protein 43; CK1, casein kinase 1; GABRA3, Gamma-amino
butyric acid receptor subunit alpha-3; SOCS3, Supressor of cytokine signaling 3; DANCR, Differentiation antagonizing non-protein coding RNA; Ryk, Receptor-like
tyrosine kinase; Daam1, Dvl Associated activator of morphogenesis 1; ROCK, Rho–associate coiled coil-containing kinase; PK-PD, Pharmacokinetic -pharmacody-
namics; SRC, sarcoma kinases; PI3K, phosphoinositide-3-kinase; mTOR, mammalian-target of rapamycin; TGF, Transforming growth factor.
* Correspondence to: Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India.
E-mail address: vdevirajeswari@vit.ac.in (V. Devi Rajeswari).
Contents lists available at ScienceDirect
Critical Reviews in Oncology / Hematology
journal homepage: www.elsevier.com/locate/critrevonc
https://doi.org/10.1016/j.critrevonc.2022.103901
Received 19 December 2021; Received in revised form 17 December 2022; Accepted 20 December 2022
Critical Reviews in Oncology / Hematology 182 (2023) 103901
2
1. Introduction
Breast cancer is one of the signicant causes of death in women
globally and one of the most commonly diagnosed cancers. (Torre et al.,
2015) According to WHO, the current statistics of breast cancer shows
2.3 million cases and 685,000 deaths in 2020. Among those, 30–40%
progress into metastatic disease (Jemal et al., 2011). Of all the cancer
deaths, breast cancer alone accounts for 25% and 15% of deaths among
women (Redig and Mcallister, 2013). In today’s environment, one out of
eight women is likely to acquire breast cancer over her lifetime if she
inherits a mutated BRCA1 or BRCA2 mutation (Chen and Parmigiani,
2007). A new denition of breast cancer subtypes was issued by the
2013 Gallen International Breast Cancer Conference.(Harbeck et al.,
2013). Breast cancer has four main subtypes concerning the receptors on
its cells, including estrogen, progesterone, and human epidermal growth
factors. Hence, the four subtypes are Luminal A, luminal B,
HER2-positive( Human Epidermal Growth factor Receptor 2), and
triple-negative breast cancer (TNBC) (Orrantia-Borunda et al., 2022).
1.1. Triple-negative breast cancer
Breast cancer is one of the most common causes of death in women
worldwide and one of the most prevalent malignancies diagnosed.
TNBC-It’s a form of basal-like breast cancer that has negative expression
of progesterone (PR), estrogen (ER), and human epidermal growth fac-
tor receptor-2 (HER2), according to the proling of gene expression
(Foulkes et al., 2010). Triple-negative cancers have poor prediction and
currently lack targeted medicines due to the absence of receptors are
two challenges associated with it. (Ovcaricek et al., 2011; Podo et al.,
2010) For better enhancement in planning, prevention, and designing
innovative, individualized treatments for this breast cancer subgroup,
we need to understand the pathological mechanisms related to the onset
and progression of TNBC, which still includes unclear association with
BRCA1(BReast CAncer gene 1). The phenotypic heterogeneity may be a
remedy (Swanton and Caldas, 2009) With the advancement of new
scientic technology today, which provides a large inventory of candi-
date DNA, RNA, and protein biomarkers, as well as an extensive range of
cell signaling pathway networks, all potential candidates for screening,
disease risk assessment, diagnosis, prognosis, therapy response predic-
tion, and personalized therapy selection, are now available.(Swanton
and Caldas, 2009). Following subtypes basal-like 1, basal-like 2,
Mesenchymal(M), Mesenchymal stem-like (MSL), and luminal androgen
receptor (LAR), Immunomodulatory (Lehmann et al., 2011). According
to Burstein, LAR and MES subtypes showed overlapping depending on
the gene expression proling of Lehmann’s (Lehmann et al., 2011;
Burstein et al., 2015) Therefore ndings of both researches indicate that
there are at least four molecular subtypes (Pistelli et al., 2014). TNBCs
have an excess clonal proportion of single gene alterations. The major
tumor genes are driver genes, according to a study published in 2012.
TP53(Tumor protein P 53), PIK3CA (Phosphatidylynositol4,5-bisphos-
phate 3-kinase catalytic subunit A), and PTEN (Phosphatase and Tensin
homolog) are among the driver genes, indicating that they were altered
at some point during TNBC development. However, these alterations are
not constant in all TNBC patients (Shah et al., 2012a). The different
subtypes have various gene and oncology pathways associated with Wnt
genes (Table 1).
1.2. TNBC and its progression to Lung and Brain Cancer
According to the reports published in breastcancer.org, brain me-
tastases affect roughly 10–15% of people with stage IV breast cancer.
Breast cancer has spread to other parts of the system in most cases,
including the bones, liver, and lungs. However, the brain is the only
location of metastasis for roughly 17% of women in this cohort (Sper-
duto et al., 2020). Women with more severe forms of breast cancer, such
as HER2-positive or triple-negative breast cancer, are at a higher risk of
cancer spreading to the brain. Luminal breast cancer patients are more
likely to develop bone metastasis, and TNBC patients are more likely to
develop lung metastasis. Lung metastasis can occur in up to 40% of
TNBC patients, contrasted with only 20% of non-TNBC patients (Sper-
duto et al., 2020).
The antagonist of Wnt Dickkopf-related protein 1 (DKK1) reduces
macrophage and neutrophil recruitment in breast cancer lung metasta-
ses in part by antagonizing cancer cell non-canonical Wnt-JNK (c-Jun N-
terminal Kinases) signaling, according to a new analysis (Zhuang et al.,
2017). Reduced Wnt-NF-κB (Nuclear factor kappa B) signaling in breast
cancer cells is also involved in DKK1’s suppression of lung metastasis.
Increased non-canonical Wnt (Wnt5a) stimulation in breast cancer cells
prevents lung metastasis by modifying transcription and splicing of
specic essential pathway-linked genes (Jiang et al., 2013).
The proclamation of breast cancer cells and its metastatic growth
makes TNBC disease incurable and is the leading cause of mortality for
the great majority of TNBC patients, therefore the spread of breast
cancer cells and subsequent metastatic growth to distant organs, most
commonly the bone, lungs, and brain represent a substantial clinical
concern. The procurement of invasive attributes through genetic and
epigenetic alterations, angiogenesis, tumor-stroma interactions, intra-
vasation through the basement membrane, continued existence in the
circulation, and extravasation of some cancer cells to distal tissues are all
stages in the metastatic spread of tumor cells, which is a complex but
inexplicable process (Jiang et al., 2013).
On the other hand, propagated cells that survive pro-apoptotic sig-
nals in their new habitat frequently remain dormant in secondary organs
over long durations of latency (Giancotti, 2013). It is well known that
metastatic cell outgrowth in a foreign tissue contextualization is a slow
and inefcient process that is thought to be the rate-limiting stage in
breast cancer metastasis (Valastyan and Weinberg, 2011). Breast cancer
cells at this stage are frequently challenging to identify and, because of a
lack of proliferation, are resistant to chemotherapy (Giancotti, 2013).
2. TNBC therapeutic concerns with existing treatments
The Chemotherapeutic associated with TNBC treatment options
entirely relies on the type of physiology acquainted with these heter-
ogenous tumors (Garrido-Castro et al., 2019). For the BL1 tumors, the
anti-mitotic and DNA-damaging agents are effective. While for the BL2
tumors, the tyrosine kinase inhibitors and agents targeted against
downstream activities of genetic alteration proved to be a very effective
therapeutic (Lehmann et al., 2016).
The mesenchymal subtype of TNBC had the highest levels of EMT
and was treated with inhibitors of sarcoma kinases (SRC), PI3K (phos-
phoinositide-3-kinase), and mTOR (mammalian-target of rapamycin).
Table 1
Gene proling showing different subtypes of breast cancer. Summary of the six
molecular subtypes of TNBC characterized by Lehmann al.,2011”(Burstein et al.
(2015)).
TNBC SUBTYPE Gene ontology
pathway (GOP)
GENES FOUND IN GOPs with Wnt
association
Luminal androgen
receptor
Steroid pathway FKBP5(Wang et al., 2008)
Androgen
metabolism
SPDEF(Noah et al., 2013)
Fatty-acid
synthesis
FASN(H.Wang et al. (2016))
Mesenchymal
stem like
EMT MMP2,SNAI2,TCF4,TWIST1,ZEB1(
Laezza et al., 2012)
Wnt/β-catenin
signaling
CTNNB1,DKK2/3,TCF4,TCFL2,
CCND2,FZD4,CAV1,CAV2(Lehmann
et al., 2011)
Basal 1 (BL1)/
Basal 2(BL2)
DNA damage CHEK1(Greenow et al., 2014),FANCA,
FANCG(Huard et al., 2014),MSH2,(
Castiglia et al., 2008)RAD21(Xu et al.,
2014)
M. Banerjee and V. Devi Rajeswari
Critical Reviews in Oncology / Hematology 182 (2023) 103901
3
TGF (transforming growth factor) and receptor proteins have been
linked to these subtypes’ invasiveness and migration (Bareche et al.,
2020). However, the heterogeneity of these tumors and the absence of
effective oncogenic targets against them have posed a substantial clin-
ical obstacle to complete pathological response (pCR). Although using
neoadjuvant conventional chemotherapeutic drugs has been linked to a
higher pCR, the introduction of MDR (Multi-drug resistant), genetic
changes, and immune resistance have all impacted treatment efciency
(Von Minckwitz et al., 2012). TNBC has been linked to decreased che-
mosensitivity to platinum and taxane-based therapies caused by irreg-
ular transcriptional activation responsible for p53 protein (related to
tumor suppressionTP53) and breast cancer gene BRCA1/2 (essential for
DNA repair) (Shah et al., 2012b). Anthracycline efcacy has been re-
ported to be affected by surface overexpression of CD73 protein. (Loi
et al., 2013).
Treatment failures and disease relapse have been linked to changed
expression of genes such as proto-oncogene Myc, p53, PIK3, PTEN,
retinoblastoma 1 (RB1), cyclin-dependent CDK4/CDKN2A, Janus
kinase-2 (JAK2), BRCA1/2, EGFR (Epidermal Growth Factor receptor),
and anti-apoptotic MCL1 (Myeloid leukemia cells protein 1) after neo-
adjuvant chemotherapy (Carey et al., 2010).]. It’s critical to compre-
hend the biomarkers linked to TNBC heterogeneity and
chemoresistance, as well as the potential methods for efcient targeting.
The BRCA signaling system has been related to DNA repair in normal
cellular function. The gene has been linked to TNBC mutations and
resistance to DNA-damaging chemotherapeutics and metastatic disease.
Inhibition of PARP1 (Poly (ADP-ribose) polymerase component of
downstream signaling that leads to DNA damage) by drugs may aid in
tumor reduction, and drug resistance reverses (for taxanes and anthra-
cyclines (Geenen et al., 2018). The overexpression of receptor proteins
like EGFR ( Epidermal growth factor receptor) and VEGFR (Vascular
Endothelial Growth factor) has also been linked to TNBC development,
invasion, dissemination, and angiogenesis (Nakhjavani et al., 2019).
Surprisingly, medicines that target these surface proteins have only
improved progression-free survival while not affecting overall survival.
Inhibition of the LAR protein (Leukocyte antigen-related), on the other
hand, enhances tumor regression and prevents TNBC metastasis (Ast-
vatsaturyan et al., 2018).
Furthermore, quiescent and proliferative breast cancer stem cells
(BCSC) have been linked to the therapeutic failure of traditional anti-
cancer drugs, Multi-Drug Resistant (MDR), disease relapse, prolifera-
tion, and metastasis in TNBC (Marinelli et al., 2020). Surface
overexpression of CD44/CD24, STAT3, and ALDH1(Aldehyde dehydro-
genase 1) has been demonstrated to create habitat colonies of BCSC due
to heterogeneous regulation with genetic/ epigenetic changes. These
proteins, along with BCSC, have been linked to TNBC therapy failure in
the BL1/BL2 subtype (Garcia-Mayea et al., 2020). Surface over-
expression of CD44/CD24, STAT3( Signal transducer and activator of
transcription 3), and ALDH1 (Aldehyde dehydrogenase) have been
demonstrated to create habitat colonies of BCSC due to heterogeneous
regulation with genetic or epigenetic changes. These proteins and BCSC
have been linked to TNBC therapy failure in the BL1/BL2 (Basal-like
subtype 1 &2) (Garcia-Mayea et al., 2020). The presence of numerous
tumor microenvironments (TME) variables such as CAF (cancer--
associated broblasts), TAM (tumor-associated macrophages), mesen-
chymal stromal cells (MSC), and extracellular matrix (ECM) has also
been shown to alter the TNBC MDR (Talukdar et al., 2019).
The MDR has been amplied by BCSC production of cytokines such
as IL6/IL8 (Interleukin 6/8) and CXCL12/CXCL7. (Yu et al., 2007) CAF
signaling has been discovered to stimulate STAT1/NOTCH3(Signal
transducer and activator of Transcription 1) (Neurogenic locus notch
homolog protein 3) and immune cells in neoplasms, resulting in
decreased medication absorption. TNBC’s MDR to platins and taxanes
are improved by MSC immunomodulation via PI3K/Akt (Protein Kinase
B) and proto-oncogene Src. Tenascin C overexpression in the ECM has
been demonstrated to upregulate Wnt/NOTCH-mediated signal
transduction, resulting in BCSC and improved MDR stabilization
(Deepak et al., 2020).
MDR has been further elevated in TNBC, similar to NSCLC(Non-small
cell lung cancer), by amplifying genes encoding export proteins such as
Pgp/MDR1 (ABCB1), MRP1(Multidrug Resistance Protein 1), and breast
cancer-resistant protein (BCRP). The MDR of anthracyclines and DNA-
damaging drugs have been linked to these three protein families (Neo-
phytou et al., 2018). In particular, research in TNBC MDR reveals a link
between ABC efux proteins, EMT initiation, and the stability of
dormant BCSC.
TNBC has been demonstrated to benet from EMT mediated by
TWIST/SNAIL/FOXC2 ( Zinc Finger protein SNAI / Forkhead Box Pro-
tein C2) in terms of immunological resistance, stemness, quiescence, and
treatment resistance (Prieto-Vila et al., 2017). Furthermore, differential
transcription of genes for cellular HIF-1 (hypoxia-inducible factor), ROS
(Proto-Oncogene, Receptor tyrosine kinase), and ALDH have been
shown to regulate tumor reprogramming and subsequent proliferation,
metastasis, and MDR in these neoplasms (Nedeljkovi´
c and Damjanovi´
c,
2019). EMT has resulted in ZEB1/CHK1(Zinc Finger E -box- binding
homeobox 1)/ (Checkpoint kinase 1) mediated lower efcacy of DNA
damaging agents against the BCSC and treatment failures due to muta-
tions or downregulation of apoptosis regulating genes such as p53 and
SNAIL. As a result, identifying and targeting BCSC-specic molecular
proteins is critical for improving the therapeutic efciency of current
chemotherapy regimens (Sun et al., 2020).
Clinical trials are being conducted to target CSC signaling pathways
linked with MDR TNBC, including Hedgehog, Src tyrosine kinase,
NOTCH, and Wnt, to ensure improved regression and eradication of the
stem cell niche (Park et al., 2019). Manipulation of oncogenetic or
epigenetic targets related to BCSC quiescence, metabolism, prolifera-
tion, and resistance, such as ERK(Extracellular signal-regulated kinase),
CDK4( Cyclin-dependent kinase 4), GAS6 (Growth Arrest -Specic 6),
IGF-1R( Insulin-like growth factor −1 Receptor), BMP4/BMP7(Bone
morphogenetic protein 4 and 7), KRAS(Ki-ras2 kirsten rat sarcoma viral
oncogene homolog), and TGF-2 (Tumor growth factor 2), has also been
investigated for chemoresistance reduction and better BCSC cell death
(Nazio et al., 2019). The interaction of increased autophagic proteins
(BECLIN1, ATG4(Autophagy-regulating protease 4),
Epithelial-Mesenchymal Transition(EMT), TME, and cellular chromo-
somal stability has further improved BCSC cell survival, and inhibitors of
these proteins are being investigated clinically for better efcacy
(Vera-Ramirez et al., 2018).
With the discovery of novel disease targets and chemotherapeutics
with single or multitargeting capabilities, a paradigm shift in the land-
scape of TNBC treatment has occurred. Although these novel medicines
have been introduced to traditional combination chemotherapy, there is
still an unmet need for effective regulated delivery of these medications
to tumor locations with temporospatial presence and lower toxicity
proles (Kalimutho et al., 2015). This necessitates the delivery of ther-
apeutic medicines to action lacunae using nanocarrier systems (Jain
et al., 2020).
3. Biomarkers for the clinical management of TNBC patients-
State of the Art regarding the clinical practice
The approved biomarkers present for TNBC are BRCA1/BRCA2, HRR
genes, Stromal TILS, PD-L1,Microsatellite Instability , PI-3-kinase
pathway,GPNMB, Trop-2,LIV-1, CA6 (Cocco et al., 2020). The PARP1
protein is required for DNA double-strand break repair in BRCA1/2
defective cells (Prakash et al., 2015). Olaparib is approved by the FDA to
treat HER2-negative TNBC that targets PARPi. Based on the phase III
EMBRACA research, the FDA has approved talazoparib for use in pa-
tients with metastatic or locally advanced HER2-negative breast cancer,
deleterious or suspected detrimental gBRCAm, or both. Clinical trials are
ongoing for Niraparib, Rucaparib, and Veliparib (Vinayak et al., 2019).
Another biomarker for TNBC is homologous recombination repair
M. Banerjee and V. Devi Rajeswari
Critical Reviews in Oncology / Hematology 182 (2023) 103901
4
(HRR). The targeted therapy uses an ATR inhibitor and a WEE 1 inhib-
itor. Ataxia Telangiectasia and Rad3 Related (ATR) Serine/Threonine
Protein Kinase are inhibited by the ATP-competitive, orally bioavailable
drug AZD6738, whereas DNA-damaging drugs are combined with the
small molecule WEE1 inhibitor AZD1775 in various trials. (Webster
et al., 2017). Three ATR inhibitors (M6620, AZD6738, and
BAY1895344) are in the early phase of clinical trials.
In TNBC, higher TILs (Tumor-inltrating lymphocytes) at diagnosis
have been associated with pathologic complete responses with neo-
adjuvant chemotherapy and enhanced survival after adjuvant treatment
(García-Teijido et al., 2016). The presence of intra-tumoral and stromal
TILs has a predictive and prognostic function. 20% of TNBC frequently
express PD-L1(Programmed death ligand 1), and this gene has been
linked to specic BC traits such as young age, large tumor size, high
grade, high proliferation, ER-negative status, and HER2-positive status.
About 10% of tumor cells (TC) express PD-L1, whereas 40–65% of
tumor-inltrating immune cells do the same. The prognostic value of
PD-L1 positive on IC has been conrmed in numerous clinical trials.
PD-L1 expression is controlled by wnt signaling. The expression of PD-L1
on tumor-inltrating immune cells (IC) may also play a function as a
biomarker as it has been demonstrated in multiple clinical trials. First in
class to receive FDA clearance, atezolizumab (anti-PD-L1) is used in
combination with nab-paclitaxel rather than nab-paclitaxel alone as
rst-line therapy for metastatic TNBC. To identify PD-L1 expression on
IC, the FDA also approved the VENTANA PD-L1 (SP142) assay (Rugo
et al., 2019; Schmid et al., 2020).
MSI-H/dMMR was the rst biomarker to provide an anticancer
medicine with a "site-agnostic" that FDA approved. Pembrolizumab was
approved for use as monotherapy on solid tumors with MSI-H or dMMR
and lacked appropriate treatment options. The FDA has approved the
use of Pembrolizumab for TNBC in combination with MSI-H/dMMR,
despite the low frequency of MSI-H/dMMR in BC (0–1.5%) and the
ongoing research into its potential value as a prognostic or predictive
biomarker (Marabelle et al., 2020).
Particularly LAR TNBC are sensitive to endocrine manipulations with
AR antagonists and are enriched (between 40% and 50%) in triggering
PIK3CA mutations(Brian D. Lehmann et al., 2014); this may make them
susceptible to PI3K inhibitors and enhance the effects of AR antagonists.
Based on these results, the oral antiandrogen enzalutamide has been
assessed with or without taselisib in the TBCRC 032 IB/II study
(NCT02457910) in patients with AR+metastatic TNBC. According to
the RNA sequencing research results, after receiving the combination
therapy, patients showed reduced expression of genes linked to mTOR
signaling and increased expression of genes related to adaptive immu-
nity (Lehmann et al., 2020) [163].
The target antigen must be expressed (or overexpressed) on the
intended cancer cell for an Antigen drug conjugate to work effectively.
As a result, a biomarker test that detects the presence (or over-
expression) of the target antigen can be used to identify patients who
may be sensitive. TNBC cells have been found to have several com-
pounds that t these criteria. The glycoprotein non-metastatic b
(GPNMB), trophoblast cell-surface antigen 2 (Trop-2), LIV-1, and mucin
1-attached sialoglycotope CA6 are the four most promising (Cocco et al.,
2020).
In aggressive tumors like TNBC or in advanced settings, where it
participates in processes like cell migration, invasion, angiogenesis, or
epithelial-mesenchymal transition, GPNMB was found to be signi-
cantly overexpressed. In addition, it serves as a biomarker of a poor
prognosis for breast cancer (Maric et al., 2013). Glembatumumab
vedotin (CDX-011), an effective ADC coupled with the
microtubule-disrupting compound monomethyl auristatin E (MMAE), is
the substance’s target (Tray et al., 2018).
Involved in cell adhesion and the epithelial-to-mesenchymal transi-
tion, LIV-1 is a zinc transporter protein downstream target of STAT3.
Ladiratuzumab vedotin (SGN-LIV1A), its target drug, had great efcacy
in preclinical studies [195] and is currently being studied in patients
with metastatic breast tumors, with encouraging results in aggressive
TNBC(NCT03310957, NCT01969643, NCT04032704, NCT03424005,
NCT01042379) (Nejadmoghaddam et al., (2019)).
SN-38, the active metabolite of irinotecan that causes DNA damage,
is connected to Trop-2, a new and promising antibody called sacituzu-
mab govitecan (IMMU-132) that targets Trop-2 (Goldenberg and Shar-
key, 2019). Results from a phase I/II IMMU-132–01 (NCT01631552)
study demonstrated Sacituzumab Govitecan-hziy’s effectiveness, with
33.3% ORR in TNBC patients who had had a lot of prior treatment.
Ladiratuzumab vedotin (SGN-LIV1A), its target therapy, had great ef-
cacy in preclinical models [195] and is currently being tested in patients
with metastatic breast tumors, with encouraging results in metastatic
TNBC (NCT03310957, NCT01969643, NCT04032704, NCT03424005,
NCT01042379 (Nejadmoghaddam et al., (2019)).
CA6 is only expressed in solid tumors, it makes a perfect target for
ADC therapy. SAR566658 is an ADC that targets CA6 and has as its
payload DM4, an anti-microtubule agent derived from maytansine.
Currently, phase II research in CA6-positive TNBC (NCT02984683) is
being conducted in light of encouraging ndings from a phase I trial
(Gomez-Roca et al., 2016).
3.1. Novel molecular pathway- clinically signicant aspects
PD-L1 is the known biomarker for TNBC (Abad et al., 2022). The Wnt
signaling is known to regulate PD-L1. The aberrant WNT signaling
pathway can interfere with cancer immuno-monitoring and encourage
immune escape. The complicated dynamics of TNBC-related immune
evasion may be inuenced by PD-L1-positive tumor components with a
stemness phenotype, which may be targeted by inhibiting WNT
signaling (Castagnoli et al., 2019). The relationship between hypoxia
and TNBC has drawn the attention of numerous researchers. Lysyl oxi-
dase (LOX), which is present in the hypoxic cancer secretome, has been
linked by Cox to the development of discrete pre-metastatic lesions in
patients with estrogen-receptor-negative breast cancer. TNBCs have
been shown to have hyperactivated HRGs and HIFs and their target gene
products, which are proven to be involved in a variety of tumoral
mechanisms, including immune evasion, resistance to treatments, in-
vasion, and metastasis. As a result, HRGs are a prospective therapeutic
target for TNBC and prognostic predictor. For TNBC, thorough evalua-
tions of the prognostic prediction models based on several HRGs are
currently lacking (Sun et al., 2021).
The metastatic property of Triple Negative cancer cell trans-
formation from the epithelial to mesenchymal is mainly because of the
Hypoxia condition and wnt signaling. As per the research in breast
cancer cells, there is an upregulation of the wnt and TWIST genes. Wnt
signaling and Hypoxia both induce Epithelial-mesenchymal transition
by regulating the SNAIL AND SLUG gene, which further governs the E-
cadherin, responsible for the epithelial-to-mesenchymal change (Martin
et al., 2005). In Breast cancer cells, HIF-2
α
converts normal cells into
stem cell phenotype, which induces chemoresistance by triggering Wnt
and Notch signaling pathways (Yan et al., 2018).
Therefore, we can conclude that Wnt signaling is linked with the
biomarkers of breast cancer and inuences metastasis and chemo-
resistance by regulating them. If targeted, the Wnt signaling could be a
solution for TNBC and be used clinically.
4. Existing therapy: chemotherapy and problems associated
Chemotherapy is the most common method of treatment for cancer.
According to published evidence, the lack of expression of ER, PR, and
HER2 genes may not be the sole cause of this disease’s fatality. While
signicant resources have been devoted to research TNBC biology and
treatment, our overall understanding of the disease’s biology remains
inadequate. Breast cancer patients’ overall survival has improved
considerably due to earlier detection and better therapies (Jang et al.,
2015; Ci et al., 2016).
M. Banerjee and V. Devi Rajeswari
Critical Reviews in Oncology / Hematology 182 (2023) 103901
5
Metastatic breast cancer, on the other hand, has a 5-year overall
survival rate of less than 30%. Despite the availability of medicines such
as cytotoxic chemotherapies, endocrine therapies, and targeted therapy
for metastatic breast cancer, the survival rate remains low. This could be
due to metastatic breast cancer’s decreased response rate to systemic
chemotherapy and higher treatment resistance (Jang et al., 2015; Koike
et al., 2017).
Numerous medicines are used in tandem with current chemothera-
peutic regimens to attack tumor cells through multiple routes, with
various such mixtures being clinically explored. However, the thera-
peutic response has been unsatisfactory due to a lack of regulated
administration and the good temporospatial presence of chemothera-
peutics. As a result, PEGylated liposomal doxorubicin and passive target
albumin-bounded paclitaxel have been clinically employed and evalu-
ated with newer medicines for better treatment efcacy in certain tu-
mors. In both neoplasms, active targeting of nanocarriers towards
surface overexpressed proteins has been investigated (Xu et al., 2017).
As Jessica et al., 2015 (Tao et al., 2015) mentioned the short-term
complication associated with breast cancer after chemotherapy are
Cytopenia, Alopecia, Chemo-Induced Peripheral Neuropathy, Neuro-
cognitive dysfunctions, Fatigue, and Pain(musculoskeletal). The
long-term complication associated with Breast cancer patient after
receiving chemotherapy is cardiomyopathy, CIPN, Neurocognitive
dysfunction, Psychosocial Impact, Second Cancers, Bone health and
cardiovascular disease, Early menopause, Fertility, Bone health, and
cardiovascular disease (Fig. 1).
5. Wnt signaling has been linked to the development of anti-
cancer drug resistance
Solzak et al. recently published studies showing that mono-agent
therapy (using PI3K Phosphoinositide 3 -kinases inhibitors) is usually
resistant to TNBCs. Consequently, using buparlisib (panPI3K) and Wnt
(Wnt-pathway) in combination therapy against TNBC cell lines and xe-
nografts showed signicant in vitro and in vivo synergy (Wang et al.,
2019). The Wnt/β-catenin pathway has also been connected to the
maintenance of PI3K drug resistance. It appears that employing β-cat-
enin inhibitors can resensitize PIK3CA (Phosphatidylinositol-4,
5-Bisphosphate 3-Kinase Catalytic Subunit Alpha) to PI3K inhibitors in
patients with PIK3CA-mutated TNBC (J. Solzak et al., 2017; Brian D
Lehmann et al. (2014)).
This has to do with increasing the sensitivity of tumor cells to com-
bination treatment medications by controlling cancer cell proliferation.
In some situations, the relationship between the Wnt pathway, tumor-
related signaling pathways, and even epigenetic modications in
advanced TNBC could result in a multidrug-resistant phenotype. As a
result, identifying the Wnt signaling network, which has yet to be
approved by the FDA for targeted therapy, is crucial for maximizing the
efciency of our current medicines. Even though numerous studies have
demonstrated that TNBCs respond well to chemotherapeutic therapies,
TNBC patients typically develop chemo-refractory illnesses with a
dismal prognosis.
Recent research suggests that targeting Wnt/β-catenin signaling in
TNBC patients in combination with chemo and targeted therapies pro-
vides highly synergistic results and inhibits Wnt signaling activity in
chemoresistance cancer cells. β-catenin reduces the viability of TNBC
cells to doxorubicin or cisplatin-mediated cell death, according to Xu
et al., in in-vitro investigations, demonstrating that β-catenin expression
correlates with TNBC chemoresistance (Xu et al., 2015). More research
is needed, however, to see if the Wnt pathway and its components may
be used as therapeutic targets in TNBC. Various mechanisms can induce
chemoresistance, with ATP-binding cassette (ABC) transporters being
the most well-studied.
TNBC has high levels of the multidrug-resistant protein-1 and −8
(MRP1 and 8), the breast cancer resistance protein ABC-super family G
member 2 (ABCG2), and the P-glycoprotein (MDR1) pump, which
pumps chemotherapeutics out of cancer cells. Previous research found
that increased nuclear and cytoplasmic β-catenin levels caused ABCB1
ABC-sub family B member 1 (MDR1 or P-GP) in TNBC with BRCA1/2
mutations to excrete PARP inhibitors (PARPi) from the cells aggressively
(Gangrade et al., 2018). As a result, combining drugs that target the
Wnt/β-catenin system to overcome PARP inhibitor tolerance could open
up new possibilities for enhancing medical outcomes.
Frizzled receptor 1 (FZD1) and P-gp overexpression boosted the
doxorubicin-resistant in breast cancer cells, according to Zhang et al.
ndings’s. According to their ndings, P-gp overexpression and
Fig. 1. Complication faced by patients suffering from breast cancer after chemotherapy (Biorender.com).
M. Banerjee and V. Devi Rajeswari
Critical Reviews in Oncology / Hematology 182 (2023) 103901
6
cytoplasmic/nuclear β-catenin levels were suppressed by inhibiting the
FZD1 gene expression with siRNA (H. Zhang et al., 2012). In multiple
investigations, disease stem cells (CSCs) are more resistant to conven-
tional therapy in TNBC, resulting in cancer survival and relapse. In
addition, hypoxia-induction has been shown to increase Wnt/β-catenin
signaling in hypoxic environments and promote β-catenin stability and
CSC transcription gene activation (Xu et al., 2017) However, no concrete
evidence has been found in TNBC to establish such a relationship.
Through a synergistic connection between Wnt target gene c-MYC and
HIF-1, which can impair cancer cell sensitivity to anticancer medica-
tions, Wnt signaling increases tumor therapeutic tolerance. (He et al.,
1998) Enhanced Wnt backed up these ndings signaling pathway acti-
vation in response to drug inactivation/detoxication, dysregulation of
DNA, damage repair pathways, cell cycle, and apoptosis (Merikhian
et al., 2021).
These signaling networks become disturbed due to aberrant activa-
tion of Wnt signaling in cancer cells, resulting in resistance to some
TNBC therapy medications. As a result, there is a compelling clinical
need to understand better how increased Wnt signaling contributes to
resistance to a variety of traditional and targeted cancer therapies, as
well as to create novel combinatorial drugs that extend the time between
TNBC disease recurrences.
6. Wnt pathway association with Tumor propagation and
signaling transduction pathways
TNBC has been found to contain many cross-talks between Wnt
signaling and other intracellular signaling pathways, which can lead to
therapy resistance. In TNBC patients treated adjuvant, gene expression
patterns of TNBC cells revealed a connection between EGFR and Wnt
signaling. Recent results on the resistance mechanisms in TNBC cells
that over-express EGFR constitutively show that inhibiting Wnt/β-cat-
enin signaling reduces the levels of β- catenin, RAS, and EGFR, sug-
gesting the possibility of combination therapy for TNBC patients (Ryu
et al., 2020). In the β-catenin is found at adheres junctions, usually
sustained by kinases, the loss of membranes β-catenin in
EGFR-overexpressing tumors could be proof of EGFR-induced cell-to--
cell adherence instability (Lakis et al., 2016). Furthermore, sufcient
evidence suggests that EGFR can directly phosphorylate β-catenin and
activate EMT in tumor cells by disrupting the connection between
β-catenin and E-cadherin, increasing tumor dissemination (W. Wang
et al., 2016). TNBC was not successfully treated with either Erlotinib (an
EGFR inhibitor) or Lapatinib (an EGFR/HER-2 inhibitor) used alone.
However, a modest dose of lapatinib did serve as a substrate rather than
an inhibitor, enabling EMT and MDR and ultimately leading to metas-
tasis. Additional gene expression investigations revealed that lapatinib
and XAV939 (a tankyrase inhibitor) co-targeted the EGFR and
Wnt/β-catenin pathways to promote mesenchymal to epithelial transi-
tion (MET). By simultaneously attacking TNBC cells’ EGFR and
Wnt/β-catenin signaling pathways, new treatment options for this con-
dition may become available (Shome and Ghosh, 2021).
The disruption of adherent junctions is caused by the interplay of
EGFR signaling with the Wnt/β -catenin pathway, which involves a
variety of kinase signaling cascades. Interaction between the Wnt/β
-catenin and EGF/RAS/ERK (Epidermal growth factor receptor/Rat
Sarcoma protein/Extracellular regulated kinase) signaling pathways, for
example, increases β-catenin nuclear translocation by inhibiting
GSKGSA-3 (Glycogen synthase kinase 3) (Caspi et al., 2008; Lemieux
et al., 2014). Wnt/β-catenin signaling, on the other hand, can control
RAS stability by lowering proteasomal ubiquitination and destruction.
RAS stabilization at the plasma membrane triggers transcription factor
activation and activates the RAF/MEK/ERK (Rapidly accelerated bro
sarcoma/Mitogen-activated protein kinase/Extracellular-signal regu-
lated kinase) (MAPK) signaling cascade, leading to hyperproliferation,
high cancer stem cell (CSC) activation, and metastasis (Robertson et al.,
2018).
7. miRNA-based therapeutics
At present, there are two strategies to miRNA therapeutics-: The
onco-miRNAs are inhibited using the miRNA antagonists directly, or
indirectly, they use miRNAs or non-miRNA targets that are known to
down-regulate the specic onco-microRNAs, & tumor suppressor-
microRNA mimetic is used to restoring the loss-of-function of tumor
suppressor-miRNAs (Teo et al., 2021).
7.1. Interconnection between microRNA and the Wnt Pathway
Dysregulation of microRNA elicits a persistently active Wnt signaling
in cancer; their expressions are widely supervised by Wnt signaling. To
nd the microRNA which regulates wnt signaling, 470 miRNAs were
screened in Human HER293 cells. The microRNA regulates the wnt
signaling pathway by binding to the ligand or the components associ-
ated with the Wnt signaling at multiple levels and hence helps in the
repression of Wnt signaling. They also interact with the β-catenin
complex and the factors associated with it (Anton et al., 2011). Wnt
activation promotes microRNA expression by coupling catenin with
TCF/LEF (T-cell factor/ lymphoid enhancer factor), which links to the
transcription components that encourage domain activation. There are
many microRNAs and Wnt signaling components that have bilateral
feedback loops. The microRNAs targeting different segments of Wnt
signaling (Peng et al., 2017).
8. Recent novel approaches MicroRNAs targeting Wnt signaling
in breast cancer
In 2019, Samira Mohammadi yeganesh proved that miR-381 regu-
lates Wnt signaling. When it was re-expressed in a mouse model
suffering from TNBC, the invasion of cancer cells to the lungs and liver
was inhibited. Therefore the survival time was more signicant (S et al.,
2019). Similarly, in 2016, she proved that microRNA −340 inhibits
metastasis in a breast cancer cell by targeting wnt signaling (S et al.,
2016). In 2018, Sanhongliu showed how some microRNA could inu-
ence the rate of Triple-negative breast cancer by targeting wnt/β
–catenin signaling, the miR-221/222 was overexpressed drastically in
all four TNBC cell lines and demonstrated that by both ex vivo and
xenograft experiments that if miR-221/222 are inhibited the prolifera-
tion, EMT transition, viability, migration will be suppressed.
microRNA-221/222 achieve this by repressing multiple negative regu-
lators of Wnt/β–catenin signaling pathway, including W1F1, SFRP2(
Secreted Frizzled-related protein 2), DKK2(Dickkopf Wnt signaling
pathway inhibitor 2), AXIN2, to activate the pathway (S et al., 2018).
In 2019, Guozhu Liu and his colleagues described that when miR-
6838–5 P is upregulated, it suppresses cell metastasis and the EMT
process in triple-negative breast cancer by blocking the Wnt pathway.
They could bind to the WNT3a and can negatively regulate WNT3A
expression (G et al., 2019). In 2019, Jun Ni and his colleague elaborated
on inhibiting the miR-125b expression directly regulated the wnt
signaling. In response, it inhibits the EMT transition and suppresses the
proliferation in TNBC cells of MDA-MB-468 (J et al., 2019; Kim et al.,
2011), explained that microRNA-145 could be used as a new therapeutic
for breast cancer (Kim et al., 2011).
In 2017, Ling-Yu kong showed that microRNA-27a could activate the
Wnt/β –catenin signaling pathway, which in turn regulates SFRP1
negatively to promote the proliferation, migration, and invasion of
Breast Cancer cells. (LY et al., 2017) Gang Wu et al. demonstrated that
microRNA-655–3p functions as a tumor suppressor by regulating
ADAM10 (Glycosylated type 1 membrane protein) and the β-catenin
pathway in hepatocellular cancer. (G et al., 2016)Therefore, we can
conclude that micro-RNA can regulate Wnt signaling and play an
essential role in inhibiting TNBC or triggering TNBC. List of miRNAs
targeting wnt/β- catenin signaling and its associated protein or different
downstream element related to wnt signaling in breast cancer (Table 2).
M. Banerjee and V. Devi Rajeswari
Critical Reviews in Oncology / Hematology 182 (2023) 103901
7
9. Understanding the miRNAs biogenesis
They are a family of noncoding endogenous RNA molecules with a
length of 22–25 nucleotides that target mRNA transcripts Micro-RNAs
(miRNAs) are one component of the non-coding class of RNA. They
are small, endogenous, universal RNA regulators of critical biological
miRNA development, which can include activation and invasiveness
(Lin and Gregory, 2015a). Current studies involving the in vivo and in
vitro on TNBC cell lines showed that miRNAs are linked with the
aggressive phenotype.
They are a family of noncoding endogenous RNA molecules with a
length of 22–25 nucleotides that target mRNA transcripts and play a
critical regulatory role. Translational repression or disintegration can
occur as a result of the regulation. The biogenesis of micro-RNAs is very
much specic in cells and tissue. In humans, mostly, they are encoded in
introns. However, their presence can also be seen in some exonic parts.
Intergenic miRNAs are transcribed by the pol ІІ and pol ІІІ producing pri-
mRNA, which is along stem-loop structured RNA stretch on both ends.
MicroRNA is created when the RNA polymerase transcribes pri-mRNAs
(Lee et al., 2003). Only miRNAs with an acceptable stem length, a large
exible terminal loop (10 bp), and the ability to produce 5’and3’
single-stranded RNA overhangs will be efciently translated and
evolved into functional miRNA. Primary miRNA precursors and mRNA
share many similarities. The most common miRNAs are polycistronic
transcripts with 7methylguanylate (m7g) caps, distinct 5 and 3’
boundaries, and poly(A) tails (Lee et al., 2002).
A microprocessor complex that consists of RNAseІІІ enzyme Drosha
and DGCR8 (DiGeorge Critical Region 8) plays a critical role while
converting clusters of pri- miRNAs into Pre-miRNAs. The conversion
occurs when Drosha cleaves 11 bp away from the single-stranded loop
junction, transforming the pri-miRNA into pre-miRNA (Hutv´
agner et al.,
2001). The pre-miRNA can be characterized as containing a 5
’
phos-
phate group and 2–3 nucleotides 3
’
overhang (Fire et al., 1998; Ham-
mond et al., 2000; Martinez et al., 2002). With the help of specic
endonuclease RNAseІІІ Dicer, the pre-miRNA is spliced to form miRNAs
when translocated to the cytoplasm. HnRNPA1(Heterogenous nuclear
ribonucleoprotein A1), SMAD1, and SMAD5 have been reported to
associate with miRNA precursors and inuence how they are processed
into nal miRNA. The protein of the Argonaute family starts the miRNA
and then joins the microRNA-induced silencing complex (miRISC). The
Argonaute family protein initiates the miRNA and is further coupled into
the microRNA-induced silencing complex(miRISC).(Hwang and Men-
dell, 2006; Shivdasani, 2006; Olivieri et al., 2013). The formation of
RISC (RNA-induced silencing complex) is responsible for the regulatory
functions of miRNAs. This miRISC further attaches to the 3
’
untranslated
region of the target mRNA. The degree and nature of complementarity
between the microRNA and the mRNA decide the fate of the further
consequences, whether it will go for slicer-independent translation in-
hibition, gene silencing mechanism, or slicer-dependent mRNA degra-
dation (Lin and Gregory, 2015b). If they are perfectly coupled, the
match will result in de-adenylation and, as a result, destruction, whereas
an incomplete matching will hinder the targeted mRNA’s translation.
Silencing happens within the P-bodies, according to recent ndings. As a
result, P bodies are required for microRNA-mediated gene silencing and
RISC assembly (Hwang and Mendell, 2006).
10. Regulatory roles of microRNAs in TNBC
In TNBC, multiple microRNAs are linked to disease progression,
including epithelial to Mesenchymal transition, cancer cells acquiring
stem-like features, motility, invasiveness, and metastatic spread.(Pia-
secka et al., 2018a).
10.1. EMT (Epithelial-to-mesenchymal transition)
EMT is considered a cellular reprogramming mechanism that plays a
crucial role in changing the cells into cancer cells, an “invasive make-
over,” and is regarded as a prerequisite for metastasis. (Sethi et al., 2011;
Seton-Rogers, 2016; Felipe Lima et al., 2016). The most fundamental
event in EMT occurs when the cell loses its E-cadherin expression, which
is required by the normal epithelial cell to maintain the integrity of the
entire cadherin-catenin-actin network. Although the transcriptional
modulation of E-cadherin expression has yet to be established, various
transcriptional factors such as SNA11/Snail1, SLUG(SNAI2 instructor
gene), ZEB1, ZEB2, E47, and KLF8 (Kruppel-like factor 8) have been
observed to bind to the E cadherin, further repressing transcription
(Felipe Lima et al., 2016; Seton-Rogers, 2016; Singh and Settleman,
2010; Lamouille et al., 2014).
Several pathways, including the WNT pathway, are altered due to
this transition. Wnt signaling is triggered in breast cancer, leading to
increased catenin levels. E-cadherin’s linkage with catenin subsequently
breaks down, which is caused by a rise in catenin levels. This is followed
by translocation into the nucleus. It promotes a mesenchymal-specic
gene prole in the nucleus.[87][88] Plenty of miRNAs were found to
be down-regulated in various cancer cells. The miRNA-200 family,
which includes miR-200a, miR-141, miR-200b, miR-200c, and miR-429,
are known for their negative regulation of EMT, distinctively targeting
ZEB1/2 (Kalluri and Weinberg, 2009; Korpal et al., 2008; J.Wang et al.,
2013; Wang et al., 2014) In vitro studies showed that miR-200 in the
family was down-regulated in TNBC cells and established
tumor-suppressive in normal tissues (Korpal et al., 2008; Mekala et al.,
2018). TNBC had lower levels of miR200 family expression than the
other subtypes of breast cancer. (Fig. 2)This microRNA family is
Table 2
List of microRNAs targeting Wnt ligands/receptors and associated proteins.
miR Target in Wnt
signaling
Effect Reference
miR-516a-3p pygo2/Wnt
pathway
Tumor
suppressor
(Chi et al., 2019)
miR-130a-3p Wnt signaling Tumor
suppressor
(Poodineh et al., 2020)
miR-221/22 Wnt/β catenin Oncogene (Garofalo et al., 2011)
miR-148a WNT1 NRP1 Tumor
suppressor
(Jiang et al., 2016b)
Targeting β-catenin
miR-200c β-catenin Tumor
suppressor
(Ahmad et al., 2012)
miR ¡340 β-catenin, ROCK1,
c-MYC
Tumor
suppressor
(Mohammadi-Yeganeh
et al., 2016)
MiR-141 β-catenin, SOX17 Tumor
suppressor
(Abedi et al., 2015)
Targeting multiple Wnt signaling components
miR-34 WNT1/3,
β-catenin, LRP6,
LEF1, AXIN2,TCF7
Tumor
suppressor
(Kim et al., 2011)(Kim
et al., 2013)
Targeting Wnt signaling related transcription factors
miR-17–5 P P130, HBP1 Oncogene (Li et al., 2011)
Targeting β-catenin interacting proteins
miR-142 APC Oncogene (Isobe et al., 2014)
miR-1229 APC, GSK3β Oncogene (Tan et al., 2016)
Targeting Wnt
ligands/
receptors and
associated
proteins
MiR-1 FZD7, TNKS2 Tumor
suppressor
(Liu et al., 2015)
miR-100 FZD8 Tumor
suppressor
(Jiang et al., 2016a)
miR-29 Demethylation of
WIF1,N-myc
interactor
Tumor
suppressor/
(Rostas et al., 2014)
miR-372/373 DKK1 Oncogene (Zhou et al., 2012)
miR-374a WIF1, PTEN,
WNT5A
Oncogene (Cai et al., 2013)
miR-218 SOST, DKK2,
SFRP2
Oncogene (Hassan et al., 2012)
M. Banerjee and V. Devi Rajeswari
Critical Reviews in Oncology / Hematology 182 (2023) 103901
8
involved in TNBC pathogenesis through various mechanisms, including
BRCA1/2, but its most crucial function is EMT control. A low level of
miR-200 leads to the absence of E-cadherin, indicating miR-200 to be a
negative regulator. Korpaland colleagues reported the correlations be-
tween miRs-200 family and EMT. Innumerable research reported that
miRNAs might function as EMT inhibitors by targeting the Wnt signaling
pathway or regulating its downstream transcription factors.
Over-expression of these miRNAs could thus be a standard therapy for
reversing EMT(Lin and Gregory, 2015b; Teo et al., 2021).
10.2. Targeting Wnt signaling downstream transcription factors
The EMT –induction transcription factors, such as suppressors of E-
cadherin ZEB, Twist, and Snail, are contemplated to be managed by the
microRNAs in numerous types of Cancer (Díaz-L´
opez et al., 2015). The
majority of them are found downstream of the Wnt signaling pathway
TGF-mediated EMT was reactivated shortly after the miR200 family’s
levels in invasive carcinoma were reduced (Lu et al., 2013; Wellner
et al., 2009). A mechanism related to miR-200 is that it inhibits Wnt
signaling. To decrease translation, the process is blocked by targeting
transcription factors ZEB1/2 and catenin binding to mRNA. Two in-
dividuals make up the ZEB family. E-cadherin interacts with ZEB1 and
ZEB2 in the promoter-based E-box DNA sequences, inhibiting tran-
scription and allowing Mesenchymal gene activation (Wellner et al.,
2009; Díaz-L´
opez et al., 2015; Piasecka et al., 2018b).
10.2.1. Wnt/β-catenin pathway- Its role in the initiation of EMT
The Wnt/β-catenin and EGFR signaling pathways are activated when
specied ligands bind to them. When Wnt ligands bind to FZD receptors,
they transactivate the EGFR signaling further by releasing EGF ligands,
which MMP mediates. The Wnt/β-catenin pathway is activated by EGFR
signaling via the PI3K/Akt and Ras/MEK/Raf/Erk signaling cascades.
Akt stimulates the production of β-catenin. Akt either causes trans-
activation or inhibits GSK-3(Glycogen synthase kinase 3) activity. PTEN
is a tumor suppressor that can also prevent Akt from activating. PTEN
negatively regulates β-catenin nuclear translocation (Suzuki et al.,
2015).
When the EGFR pathway is activated abnormally, dissociation from
α
-catenin causes an enhancement in the free β-catenin in the cytoplasm;
the transcription factors ZEB, SNAIL, and TWIST are all linked to EMT.
Many signaling pathways exist that promote the production of these
transcription factors, causing tumor cells to proliferate and spread. The
phosphorylation and activation of JAKs and the activator of transcrip-
tion proteins are triggered by the interaction of numerous growth factors
and cytokines with their receptors (STATs). STAT3/5 dimers activate
transcription factors linked with genes encoding EMT, anti-apoptotic,
and longevity proteins (Fig. 3).
When a stimulus is presented, substances such as TNF-
α
, the IKK (IKB
kinase) complex is activated, resulting in the phosphorylation of IKB
(Inhibitor of nuclear factor kappa B) and its destruction by the protea-
some, as well as NF- κB(Nuclear factor kappa B) migration into the nu-
cleus. Wnt signaling initiates PI3K/Akt/mTOR in an EGFR- dependent
manner. It also identied β-catenin in the nucleus as well as EGFR target
genes. Akt can cause nuclear trafcking of β-catenin and inhibit GSK-3 β
activity, leading to enhanced transcription of proliferative genes and
tumor cell invasion (Moradi-Kalbolandi et al., 2018). Reduced expres-
sion of PTEN, a tumor suppressor mediated by Akt signaling, arbitrates β
catenin translocation to the nucleus and explains the subclass of
extremely deadly TNBCs with PTEN-low that should be considered
aggression (Mccubrey et al., 2014).
The improved investigations have concentrated on Wnt/ROR
signaling and its impact on tumor cell activity, which begins with the
activation of non-canonical Wnt signaling by binding of Wnt5A ligand to
two receptor tyrosine kinase-like orphan receptors (RORs), ROR1 and
ROR2 (J. P. Solzak et al., 2017; Menck et al., 2021). The current study
explains the involvement of Wnt5A/ROR1 signaling in TNBC tumor cell
metastasis via phosphorylation of ROR1 by multiple kinases, which
causes anti-apoptotic pathways to be blocked and pro-survival signaling
of Wnt/PCP, MAPK/ERK, PI3K/Akt/mTOR, TGF/SMAD, and NF-κB to be
stimulated. These pathways result in a negative role for the
Wnt5A/ROR1 signaling axis, which has been associated with increased
tumor cell metastasis and stimulates the production of genes that
contribute to cell proliferation, survival, EMT, and therapy resistance
(Lopez-Bergami and Barbero, 2020; Medina et al., 2020). Undoubtedly,
the recent development of various methods targeting Wnt 5A or the
ROR1 will benet the therapy of TNBC.
Fig. 2. Metastatic cascade in breast cancer(EMT) -The metastasis to body organ like brain and lungs (Biorender.com).
M. Banerjee and V. Devi Rajeswari
Critical Reviews in Oncology / Hematology 182 (2023) 103901
9
11. Wnt/β-catenin pathway in breast cancer
Several pathways regulate most cancer cells, including the Wnt/β –
catenin pathway. This pathway is one of the core pathways best char-
acterized so far. These pathways regulate the development, self-renewal,
and cell fate and division (Borah et al., 2015). The wnt/β-catenin path
can be manipulated and can provide an excellent therapeutic target
(King et al., 2012). Wnt signaling can be classied into two path-
ways-Wnt/β-catenin pathway (canonical pathway); the non-canonical
way can be further divided into PCP (planar cell polarity) pathway
and Wnt/Ca
+
pathway (Shakhova and Sommer, 2013).
11.1. The Wnt/β-Catenin pathway
This pathway is best characterized among the other three pathways.
This pathway is also referred to as β-catenin dependent pathway. Two
models are present in Wnt/β-catenin signaling (Muzny et al., 2012).
11.1.1. According to the classical model
11.1.1.1. Absence of Wnt stimulation. When Wnt signaling is absent,
catenin is sustained at a reduced scale owing to ubiquitin proteasome-
mediated destruction. A multiprotein destruction heterogeneous com-
plex containing Axin, glycogen synthase kinase-3 (APC) Adenomatous
polyposis coli regulates the breakdown.(Clevers, 2006) By phosphory-
lating Ser45, β-catenin is primed by casein kinase (CK1). The primes are
for destruction, which further activates Glycogen synthase Kinase 3
(GSK3), which phosphorylates β-catenin at Ser33, Ser37, and Thr41 (Wu
et al., 2009). The E3 ubiquitin ligase TrCP’s propeller domain binds with
the residues of phosphorylated catenin, further ubiquitinating it and
thereby directing it for proteasomal destruction (Liu et al., 1999)
(Fig. 4).
11.2. Presence of Wnt stimulation
When the Wnt ligand and Fzd receptor proteins join with either
LRP5/6 or LRP7, a ternary complex is formed, which activates the
pathway. The activation of kinases occurs due to the ligand binding
upstream, which causes the serine phosphorylation in the cytoplasmic
domain of LRP5/6. A single motif that is phosphorylated is enough to
trigger the wnt signaling (Tamai et al., 2004; MacDonald and He, 2012).
Both interact to destabilize the catenin destruction complex, which
consists of Axin, which acts as a scaffold for Dvl, Adenomatous polyposis
coli (APC), and glycogen synthase kinase 3, as well as the
serine-threonine kinases casein kinase 1/ (CK1) (Clevers, 2006). Catenin
levels rise and accumulate in the cytoplasm before transporting it to the
nucleus. The rise is due to the destabilization of the destruction complex,
Fig. 3. Wnt/β- Catenin pathway-: Its role in the initiation of EMT.(Biorender.com).
Fig. 4. In the absence of Wnt stimulation (Canonical Wnt/β- catenin pathway)
Classical model (Biorender.com).
M. Banerjee and V. Devi Rajeswari
Critical Reviews in Oncology / Hematology 182 (2023) 103901
10
which further eliminates the phosphorylation of β-catenin (Aristiza-
bal-Pachon et al., 2015). Inside the nucleus forms a heterogenous
complex with members associated with T-cell transcription factors
(TCF/LEF). It disperses the transcriptional repressor Groucho, which
then recruits the co-activators cAMP and response element binding
protein (CBP) or its homolog p300, as well as other components of the
basal transcription machinery (such as CtBP, Foxo, and TN) to start the
transcription of Wnt target genes (Roose et al., 1998). The binding of
CBP and p300 triggers the Wnt pathway. This pathway corroborates the
formation and sustains the CSCs, thereby forming cancer (Bordonaro
and Lazarova, 2015). As a result, over-expression or mutation in any
necessary element might result in malignant development. (Fig. 5).
The second pathway, which is not dependent on Daam1, is through
the Dvl’sd DEP domain, which activates the RacGTPase further (Lawson
and Burridge, 2014). After being activated, Rac, in conjunction with
Rho, increases JNK activity, which is crucial for cell polarisation and
directional migration (Fig. 6).
11.3. According to the new model (Azzolin et al., 2014)
The presence or lack of Wnt activation is accountable for stabilizing
the destruction complex by axin in this scenario. Newly produced cat-
enin is deposited in the cytoplasm before nuclear translocation.
Immuno-precipitation showed that when Wnt was activated, catenin
phosphorylated at Ser33/Ser37/Thr41 was associated with the
destruction complex (Li et al., 2012). The interaction of phosphorylated
β catenin and destruction complex also leads to the destruction of β-TrCP
with the Axin1-β-catenin. Recent researchers have discovered that after
Wnt activation, GSK3 inhibition and catenin translocation are commu-
nicated via GSK3 sequestration inside multi-vesicular endosomes
(Taelman et al., 2010). Wnt signaling becomes even more complicated
as a result of this.
11.3.1. Non-canonical model
The non-canonical model is further separated into two categories.
a) Planar cell polarity (PCP)
This pathway does not depend on β-catenin. It is the non-canonical
pathway. They primarily regulate the cell’s cellular organization and
polarity of cells through the Cytoskeletal organization (G´
omez-Orte
et al., 2013). In these pathways, receptors such as Wnt4, Wnt5a, and
Wnt11 bind to the FZD receptors and co-receptors, including ROR, Ryk
(Receptor-like tyrosine kinase), and PTK(Protein tyrosine kinase)
(Nishita et al., 2010). In the PCP pathway, the signal is transduced to
(Dvl) after the ligand binding to the receptor, which triggers it. Conse-
quently, Dvl interacts with Rac1, which initiates c-jun-N-terminal ki-
nase, leading to actin polymerization (Li et al., 1999). The interaction of
the Dvl-associated activator of morphogenesis 1(Daam1) to the PDZ
domain of Dvl triggers Rho GTPase, leading to the initiation of the pro-
tein known as Rho–associate coiled coil-containing kinase (ROCK) and
also myosin, which regulates cellular cytoskeletal arrangements (Habas
et al., 2001). G proteins and Dvl, initiating the Wnt/Ca
2+
pathway
(Wong et al., 2003). It also activates Phospholipase C, which causes IP3
(inositol triphosphate) to allow Ca
2+
to be freed from the endoplasmic
reticulum. Calcium release causes calcium to accumulate in the intra-
cellular space, triggering various Ca2 +-sensitive proteins, including
Protein Kinase C. (Antara De, 2011; Ishitani et al., 2003b). They also can
inhibit the canonical Wnt pathway (Dejmek et al., 2006). There are
many different results because of other turn-out pathways triggered by
ligands associated with Wnt and discovered to imbricate with the PCP
constitutes (Ishitani et al., 2003a) (Fig. 7).
a. Wnt/Ca
2þ
pathway
Wnt ligand binds to FZD, which inter-connects with According to the
new model (Azzolin et al., 2014). The presence or lack of Wnt activation
is accountable for stabilizing the destruction complex by axin in this
scenario. Newly produced catenin is deposited in the cytoplasm before
nuclear translocation. Immuno-precipitation showed that catenin
phosphorylated at Ser33/Ser37/Thr41 was associated with the
destruction when Wnt was activated Complex (Li et al., 2012). The
interaction of phosphorylated β catenin and destruction complex also
leads to the destruction of β-TrCP (β-Transducin repeat-containing
protein) with the Axin1-β-catenin. Recent researchers have discovered
Fig. 5. In the presence of Wnt stimulation in canonical (Wnt/β- catenin pathway) (Biorender.com).
M. Banerjee and V. Devi Rajeswari
Critical Reviews in Oncology / Hematology 182 (2023) 103901
11
that GSK3 inhibition and catenin translocation are communicated via
GSK3 sequestration inside multi-vesicular endosomes after Wnt activa-
tion (Taelman et al., 2010). Wnt signaling becomes even more compli-
cated as a result of this.
12. Potential receptors of Wnt signaling, which can be used for
targeting by microRNA
12.1. Wnt ligands/ proteins
Wnt proteins comprise the signaling molecules that can organize and
inuence an innumerable cell’s biological and developmental process.
These proteins are mostly found linked with the membranes of the cell
and extracellular matrix. The proteins are hydrophobic in nature. To
date, in mammals total of 19 members of the Wnts have been identied,
which have amino acids ranging between 350 and 400 in length and are
distinguished by a conserved fold of motif composed of 24 cysteine
residues (Cadigan and Nusse, 1997). The Wnt ligands are redesigned by
lipidation. Membrane-bound –O-acyltransferase porcupine adds the
palmitoyl group to a conserved serine (Gao and Hannoush, 2014). In the
endoplasmic reticulum, these proteins become palmitoylated when
acyltransferase porcupine is present in the wnt-producing cell. Palmitate
modication has been shown to improve ligand reception. Lipidation is
required for ER secretion and the Wnt function (MacDonald et al., 2014).
The lipidation occurs at Cys77 of Wnt 3a. However, the crystallographic
(Janda et al., 2012), alteration (MacDonald et al., 2014), and Imaging
Fig. 6. Planar cell polarity (PCP) pathway in a non-canonical model of WNT signaling.(Biorender.com).
Fig. 7. Wnt/ Ca
2+
pathway in non- canonical model of wnt signaling.(Biorender.com).
M. Banerjee and V. Devi Rajeswari
Critical Reviews in Oncology / Hematology 182 (2023) 103901
12
(Gao and Hannoush, 2014)studies have disapproved the lipidation at
cysteine.(Willert et al., 2003) Proteins are transported and secreted
utilizing secretary vesicles with the help of multi-pass trans-membrane
proteins Wnt less/Evi, which are found in the Golgi or on the plasma
membrane. After passing, they are associated with the Frizzled Re-
ceptors (Verkaar and Zaman, 2010; Rosso and Inestrosa, 2013).
12.2. FZD receptors
Frizzled receptors have motifs made up of conserved motifs and
comprise ten cysteine residues (Dijksterhuis et al., 2014). It also contains
seven-transmembrane domains. The FZDs include the family of class F
and G protein-coupled and smothered receptors. No complete structure
is dened for any FZD, but Smo structures are well-dened (Janda et al.,
2012). CRD and seven transmembrane regions are thought to be part of
the likely structure of FZD (Byrne et al., 2016). There are nearly 19 Wnt
and ten Frizzled receptors in the human body. The LRP5 and LRP6
co-receptors, and also ROR and Ryk, are associated with Wnt Signaling
via Fzds (Verkaar and Zaman, 2010). The unusual interaction involving
the direct binding of Wnt lipid to a binding site on one side of the CRD
(the thumb region), as well as the binding of the region from cysteines
19–22 of Xwnt8 to the other side of CRD (Takada et al., 2006), was
shown in the crystal structure of XWnt 8 in complex with the mouse
FZD8 CRD.
12.3. Low-density lipoprotein receptor 5/6
LRP5/6 (low-density lipoprotein receptor5/6) is a trans-membrane
receptor with a long extracellular tail and a large extra-cellular
domain required for binding. The four propellers are alternated with
epidermal growth factor repetitions, followed by three LRP type A re-
peats, which make up the extracellular domain of LRPs (MacDonald and
He, 2012). Although the Wnt3 and Wnt3a are bound to the second
repeat (P1E1-P2E2), the maximum of Wnts binds to the rst β-propeller.
Dickkopf restrain Wnt3 and Wnt3a binding to LRPs in a competitive
manner (Xu et al., 2022). Wnt activation causes phosphorylation via
GSK3 and CK1. According to current studies, the intracellular PPPSPxp
motifs of LRP5/6 are phosphorylated, which then recruits the axins; the
intracellular function of LRP5/6 is still unknown (Zeng et al., 2008;
Wong et al., 2003).
12.4. Disheveled
Dvl 1/2/3 shares a high level of similarity in the sequence overall
(Daniel et al., 1994). The excellent structure of Dvl consists of the DIX,
PDZ, and DEP domains. Although the unknown structure separates these
three domains, some functional signicance has been attributed to
conserved sequences within the unstructured sections (ChanGaoYe--
GuangChen, 2010; Fiedler et al., 2010). Any mutations lead to the
suppression of the Wnt signaling. Wnt signaling is suppressed as a result
of any modications. Mutations in the DIX domain’s polymerization
interface (V67A, K68A, Y27D) and the DEP domain’s polymerization
interface (E499G, D460K, G436P, K438M, D449I, and D452I) can reduce
WNT signaling (Gammons et al., 2016). The PDZ domain of DVL in-
teracts with the preserved motif in the FZD c terminal. Still, the
inter-communication between them is weak, and they are supplanted by
the interaction between the DEP domain with FZD (Hing-C et al., 2003).
According to recent investigations, the Wnt signalosomes are assembled
via domain swapping when the DEP domain binds as a monomer to the
FZD. Dvl, with the support of RNF43(Ring nger protein 43), promotes
FZD degradation by ubiquitination (Jiang et al., 2015). This shows that
the Dvl plays an antagonist role in Wnt signaling.
12.5. ROR family receptor tyrosine Kinases
They contain two conserved members, ROR1 and ROR2 (Minami
et al., 2010). In Wnt5a-mediated signaling, ROR is involved ROR2, and
when bound to Wnt5a, it initiates homo-dimerization, which stimulates
auto-phosphorylation at Tyr646. The studies show that both Wnt5a and
Wnt3a can bind to ROR2, but only Wnt5a initiates & facilitate the ROR2
signaling cascade (Liu et al., 2008). TNBC cells have high expression of
ROR1, which interacts with CK1 (casein kinase 1) and promotes tumor
growth and survival when encouraged with Wnt5a activation. It acti-
vates the phosphoinositide 3kinase (PI3K)/AKT signaling pathway (S.
Zhang et al. (2012)).
12.6. DEAD –box helicases
The ATP-binding domain of DEAD-box helicases is termed after a
preserved amino acid sequence (Asp-Glu-Ala-Asp). This amino acid is
part of an ATP-dependent DNA/RNA helicase family, which is extremely
preserved (Jarmoskaite and Russell, 2011). Their structure is compa-
rable to that of the recA, A DNA recombination protein from bacteria
since they both have an evolutionarily preserved helicase core and two
domains (Samatanga and Klostermeier, 2014). Translation initiation,
pre- and posttranslational variations, DNA repair, microRNA(miR)
processing, ribosome synthesis, and RNA decay are all signicant
functions of these multifunctional proteins (Rocak and Linder, 2004).
DDXs also have been connected to breast tumorgenesis and cancer stem
cell (CSC) stimulation via various pathways along with the wnt signaling
pathway (Linder and Jankowsky, 2011; Li et al., 2008).
13. Wnt pathway in breast cancer & triple-negative breast
cancer
The Wnt pathway was activated in breast cell lines after treatment
with Wnt ligands, which resulted in a considerable increase in cell
motility. By cutting down the Wnt ligand, Dvl, or catenin, researchers
could signicantly reduce breast cancer cells’ aggressiveness. Of all the
molecules involved in Wnt signaling, the β –catenin is the most studied
and suitable biomarker in breast cancer which shows the activation of
the Wnt pathway (Khramtsov et al., 2010). The Wnt pathway’s down-
stream molecules have been discovered to play a critical role in primary
breast cancer (Bilir et al., 2013). However, there are still components in
the pathway that also plays an important role, Axin2 polymorphism,
gene expression of APC casein Kinase 1
α
, GSK-3 β, and protein phos-
phatase 2 A; these all are the components of the destruction complex and
found to be linked with the breast cancer (L´
opez-Knowles et al., 2010; C.
Wang et al., 2013). The Wnt receptor linked with the Fzd7 pair of the
ligand is also up-regulated, and targeting this receptor affects the growth
of cancer. Hence the receptors perform a crucial role. The abnormal
expression of the co-receptors LRP5/LRP6 in cells has been linked to
mammary gland cancer. Silencing this co-receptor also inuences cell
growth, proliferation, etc. (Pohl et al., 2017).
In TNBC, the wnt’s associated molecules impact the high grade, poor
prognosis, and metastatic diseases (Geyer et al., 2011). The Wnt
pathway highly inuences metastasis associated with phenotypes, and
when it activates, it exacerbates the risk of brain and lung metastasis,
specically in TNBC patients (Fevr et al., 2007).
14. Nanocarrier alternatives to conventional therapy
Nanocarrier-associated drug delivery has long been related to cancer
treatment, and it has been extensively investigated for treating the many
unmet clinical demands associated with each neoplasm. Using
nanocarrier-based delivery of the medicines, effective translation of
traditional combination medication therapy with increased PK-PD
(Pharmacokinetic -pharmacodynamic) proles and spatial and tempo-
ral presence at the tumor site can be achieved. Importantly, for desired
therapeutic effects after systemic administration, the controlled delivery
of the medications throughout transit to the tumor cells and within the
tumor cells must be ensured. S. Ghosh et al. demonstrated that using
M. Banerjee and V. Devi Rajeswari
Critical Reviews in Oncology / Hematology 182 (2023) 103901
13
nanocarriers for anticancer drug delivery results could improve circu-
lation half-life and bioavailability, resulting in more efcient drug pre-
sentation at the targeted action areas (Gowda et al., 2013).
PEGylation-associated surface manipulation of these nanocarriers
has provided the regulated administration of treatments with stealth-
mediated passive targeting chances to the tumor cells with reduced
systemic access to the normal tissues. As part of combination therapy,
many biodegradable and biocompatible lipid and polymer-based
passively targeted nanoparticulate formulations have been studied
preclinically and clinically. Due to their controlled release, enhanced
safety, and efcacy characteristics, various drug delivery vehicles have
substituted naive medicines for the established conventional therapy
against numerous solid cancers (Moreno-Aspitia and Perez, 2005).
These nano-formulations have indeed been studied in the clinic for the
administration of chemotherapeutics, resulting in EPR (enhanced
permeation and retention) mediated selective controlled drug delivery
to the intended locus of action with lowered dose and toxicity proles
(Mukherjee et al., 2016). In place of conventional drug solutions,
pegylated liposomal Doxorubicin (DoxilTM, LipodoxTM) and nano-
particulate albumin-based paclitaxel treatment (AbraxaneTM) have
been clinically employed in established combination chemotherapies
against TNBC. Additionally, stimuli sensitized (thermal/magnetic)
nanocarriers and surface engineering for active targeting to overex-
pressed surface receptors or proteins uniquely linked with these tumors
may aid site-specic medication delivery (Li et al., 2016; Biswas et al.,
2013).
15. Recent research showing nanoparticles & microRNA used to
treat different cancer
In 2013, Xiaomeng and colleagues described that miR-29b conju-
gated with anionic lipopolyplex nanoparticles could be used to treat
acute myeloid leukemia (X et al., 2013). Ida Franiak- Pietryga and col-
leagues in 2017 demonstrated that nanoparticles could block Wnt/β
–catenin signaling (Miller-Kleinhenz et al., 2018). In 2020, Danielle M.
Valcourt and Emily S Day described how conjugated miRNA nano-
carriers/Antibody targeting miR-34a and Notch Signaling in
Triple-Negative Breast Cancer could inhibit metastasis (DM and ES,
2020). An article by Chao Han demonstrated that microRNA-1 could
inuence and down-regulate many signaling pathways, including the
Wnt pathway. Many functional studies showed that miR-1 shows
anti-tumorigenic activity. In colon cancer, microRNA-1 inhibits cell
proliferation which exhibits dysregulated Wnt signaling. It is a tumor
repressor gene (Han et al., 2014). In 2017 Emilie Indersie and her
co-workers demonstrated how microRNA therapy inhibited hepato-
blastoma growth by targeting the wnt signaling. She showed that
miRNA mimics (miR-624–5p) inhibited CTNNB and down-regulated the
metastasis and invasion (Indersie et al., 2017). An article by Rei Mizuno
explained how Let-7 µm could be a new therapeutic tool to treat Colo-
rectal Cancer. Similarly, in 2018 Krajewska demonstrated that
miRNA-34 could be used to treat colon cancer (Mizuno et al., 2018).
The WNT1 gene can act as a target for miR-122 in Hepatocellular
Carcinoma, as described by Zeinabin 2016, and after miR-122 was
elevated, notably, WNT1 expression was decreased (Ahsani et al., 2016).
Nanoparticles with siDCAMKL-1 were seen to inhibit colorectal cancer
by increasing microRNA-144. Process dependent on notch signaling and
targeting notch-1 receptor (Sureban et al., 2011). Ashrazadeh, in 2020
stated that miR-93 affects the proliferation and invasion of cancer cells.
It acts as an oncogene as well as a tumor repressor (Ashrazadeh et al.,
2020).
I-Shan Hsieh and his co-workers published an article demonstrating
that microRNA-320 suppresses metastasis similar to stem cell properties.
They observed that microRNA- 320 targets the Wnt/β–catenin signaling
pathway. The stem cell’s markers were drastically reduced. The down-
regulation of the Wnt pathway was also observed (Hsieh et al., 2013).
Other similar studies by Wei et al. also described that microRNA-
219–5p inhibits the invasion, proliferation, and migration of cells. The
microRNA-219–5p targets the wnt/ β- catenin and twist signaling. This
was observed in epithelial ovarian cancer cells. [189] Many microRNAs,
when down-regulated, also trigger cancer. One example is microRNA-
30d, which promotes cell proliferation and invasion in colorectal car-
cinoma. miR-365 inhibits cell invasion in TNBC, tag directly targeting
the 3’-UTR of ADAM10 mRNA (Liu et al., (2019)).
In 2019 Y-Y Li et al., demonstrated how miR-92b was able to inhibit
the EMT transition by targeting GABRA3 (Gamma-amino butyric acid
receptor subunit alpha-3) directly binding to the 3’-UTR region (YY
et al., 2019). MicroRNA-761 can induce metastasis in TNBC by inu-
encing the expression of TRIM29 (GC et al., 2017). In 2016 Naoshad
Muhammad et al. described that Anti-miR-203 inhibits the cancer
growth of Breast cancer by targeting SOCS3(Suppressor of cytokine
signaling 3) (N et al., 2016).
Therefore, we can conclude that many experiments have shown how
microRNA has played an essential role in inuencing signaling by tar-
geting the receptors and inhibiting cancer. Similarly, this method can
also become vital for treating TNBC. Many experiments with microRNA
targeting different signaling have taken place and were seen to be a
breakthrough in stopping the cancer progress. Many scientists have used
microRNAs to target Wnt signaling in TNBC, but only a few positive
results have been recorded. Yet, many explorations are needed, which
can add new insight into cancer’s central molecular and biochemical
processes. Hence, it can help us to have a better perspective of TNBC.
16. Nanoparticles-mediated RNA Interference of Wnt signaling:
a new therapy for cancer
One of the methods to suppress β-catenin and other vital targets in
the Wnt signaling pathway is the use of siRNA or miRNA to initiate
RNAi- mediated gene silencing. Abrams and his colleagues showed that
lipid nanoparticles containing Dicer substrate siRNA could efciently
inhibit β-catenin by targeting CTNNB1 (Catenin-β1), which codes for β
catenin. This formulation showed an effect on the mice models having
hepato-cellular carcinoma dependent on Wnt signaling (Ganesh et al.,
2016).
Similarly, Vaidya et al. developed a method to deliver long non-
coding RNA incorporated with polymeric nanoparticles targeting the
gene DANCR (Differentiation antagonizing non-protein coding RNA) to
triple-negative breast cancer (TNBC). These nanoparticles achieved
80–90% knockdown of DANCR expression in MDA-MB-231 and BT549.
The expression of β-catenin and other proteins involved in EMT and
apoptosis was seen to be decreased (Vaidya et al., 2019).
Ma et al. showed how photodynamic therapy was stimulated when
Wnt-1 siRNA conjugated with nanoparticles of polyethylene glycol-
polyethyleneimine-chlorine 6 was directed to the oral cancer cells.
The activation of Photodynamic therapy hindered the EMT transition. In
vitro studies also conrmed that the nanoparticles successfully inhibited
Wnt-1 and βcatenin (Ma et al., 2017). Similarly, Tangudu et al. evolved
PEG-polyglycidalnethacrylate nanoparticles to transport short hairpin
RNA (shRNA) or microRNA to different types of cancer. He showed that
the nanoparticles conjugated with miR-105 and microRNA-200c could
silence the expression of β-catenin and c-Myc in Jurkat cells. Further, he
also indicated that when the mouse model having colorectal cancer was
given the oral treatment of the nanoparticles containing microRNA, they
were able to delocalize β-catenin from the nucleus to the cytoplasm,
indicating inhibition of Wnt signaling (Tangudu et al., 2015).
Therefore, enabling selective inhibition of wnt pathway targets could
transform cancer management, but it is very challenging to achieve. As
newly discovered nanoparticle platforms are coming for the delivery of
RNA, RNAi can be used to regulate Wnt signaling. In the future, it will
yield an impressive outcome as well. The si-RNAs are explored more
comparatively with the micro-RNA. Many micro-RNA conjugated
nanoparticles showed a positive result in ceasing other cancer. In TNBC,
few experiments have been done using conjugated nanoparticles
M. Banerjee and V. Devi Rajeswari
Critical Reviews in Oncology / Hematology 182 (2023) 103901
14
targeting the Wnt signaling. This need to be explored more, as wnt
signaling proved that it is a crucial pathway that plays a vital role in
developing the TNBC.
17. MicroRNA delivery through nanoparticles
Various methods are present by which miRNA-loaded nanoparticles
are prepared. Among such are double emulsions, interfacial polymeri-
zation, and nano-precipitation. The constituent of the desired surface
material selects the most suitable technique (Rao and Geckeler, 2011).
Emulsication methods helped to prepare monomethoxy (polyethylene
glycol)- poly (D, L- Lactide –co-glycolide)-poly (L-Lysine)-lactobionic
acid. Through precipitation, polymer nanoparticles can be prepared
(Mohamed et al., 2019). The biomaterial of the nanoparticle encapsu-
lating MicroRNA is very much important. To adjust to the external
conditions, the biomaterials developed now are
stimuli-stimuli-responsive changes according to the external conditions.
(Table 3) (Griset et al., 2009).
17.1. Synthetic polymers
They are easily transported within the cell cytoplasm and can easily
target the receptors. Some of the examples of synthetic polymers are
PEIs (Polyethylenimine), (Lee et al., 2013) PLGA(Poly
Lactoc-Co-Glycolic acid) (Cosco et al., 2015; Ibrahim et al., 2011), PCL
(Polycaprolactone) (Cosco et al., 2015; Saraiva et al., 2018), PU (Poly-
urethane) (Liu et al., 2013; Saraiva et al., 2018). PEI protects the nucleic
acid from being degraded inside the endosomal vesicles. It also shows
weak base buffering properties (Liu et al., 2013). In colon cancer, they
have been used to deliver miR-145 and miR-33a and were seen to show
anti-tumor properties. The local or systematic administration showed
they could be a promising method to cure cancer because they showed
better metastasis inhibition than the control (Chiou et al., 2012).
microRNA-145 was delivered using PEI in the breast cancer cell line
(Yang et al., 2012). The nanoparticles blended with PEI and PEG are
surface-modied, showing less toxicity and improved bio-distribution
(Jokerst et al., 2011). Zhang et al. demonstrated that in prostate can-
cer, miR-145 could be delivered through branched PEI-PEG NPs (Wong
et al., 2007; Zhang et al., 2015). The branched chains of PEG were
surface-modied using polyarginine. Therefore, the uptake of nano-
particles was easy. Synthetic polyesters, such as PLGA and PCL, show
lower toxicity when compared to PEI because of their biodegradability
(Wong et al., 2007). Wang et al. used PLGA-PEI nanoparticles to
co-transport miR-542–3p and doxorubicin (DOX) in triple-negative
breast cancer cells. PLGA-PEI nanoparticles with association with their
cytotoxicity increases in breast cancer cell lines (S. Wang et al., 2016a;
Serrano et al., 2004). PU-based nanoparticles showed more versatile
physical and chemical properties and are also biocompatible.
17.2. Natural polymers
Polymers derived from animals or vegetables are natural polymers.
Examples are HAs (Hyaluronic Acid) and CS(Chitosan) (Prabaharan and
Mano, 2008). The CS extracted from chitin is non-cytotoxic, non--
immunogenic, and biocompatible (Hu et al., 2013). They have proton-
ated amino acids at higher pH, interacting with the microRNA, which
has an opposite charge and is highly loaded (Bernkop-Schnürch and
Dünnhaupt, 2012). The strong interaction of the polymer with the
oligonucleotide makes it less feasible to be utilized as the transport agent
because they fail to unload. Hydrophobic moieties have been conjugated
to CS to avoid the hurdle, further weakening the polymer/nucleic acid
interaction and enhancing the cytoplasmic drug delivery (Santo-
s-Carballal et al., 2015).
HAs are hydrophilic anionic polysaccharides derived naturally
(Layek et al., 2015; Layek and Singh, 2012). HA receptors recognize
those on cells. (Layek et al., 2015; Sekhon and Kamboj, 2010a). HA is
covalently grafted to cationic polymers or lipids used to deliver nano-
particles (Layek and Singh, 2012).
17.3. Inorganic nanoparticles
They have relatively small sizes and controlled morphology and are
biocompatible. Examples of inorganic nanoparticles are gold, silica, iron
oxide, and calcium phosphate (Sekhon and Kamboj, 2010b; Sekhon and
Kamboj, 2010a, 2010b). The iron-oxide nanoparticles are used for im-
aging purposes. Combining magnetic Nanoparticles with cationic com-
pounds is needed to achieve high MicroRNA encapsulation (Mulens
et al., 2013).
Silica Nanoparticles and mesoporous silica nanoparticles have been
used to deliver anti- miR-221 and Temozolomide to treat drug-resistant
glioma cells. They were used because they were biocompatible and
stable (Banik and Basu, 2014; Bertucci et al., 2015). Calcium phosphate
nanoparticles are used through DNA-Cap co-precipitation to deliver
nucleic acid effectively into the cells. They remain enclosed inside the
endosomal vesicle, which later is degraded by the lysosomal activity
releasing the content into the cells (Banik and Basu, 2014). Ghosh et al.
created a gold nanoparticle with less toxicity that can deliver microRNA
through intracellular systems and endocytosis (Ghosh et al., 2013; Zhao
and Huang, 2014).
17.4. Lipid-based nanoparticles
MicroRNA is loaded into the cationic or neutral lipids and the PEG
(polyethylene glycol) (Zhao and Huang, 2014). The cationic lipid causes
cell toxicity which can lead to the further disruption of the cell mem-
brane, and, in turn, it reduces cell activity also. To lessen the cytotox-
icity, neutral lipids such as cholesterol and DOPE PC is used (Cheng and
Lee, 2016; Hsu et al., 2013). They also increase stability as well. The
interaction between the positive (cationic) lipids with the negative
microRNA makes them so condensed that they are protected from
enzyme degradation (Hsu et al., 2013). PEG plays an important role
when combined with the lipid nano-particle it increases the half-life.
PEG plays an important role when combined with the lipid
nano-particle it increases the half-life.
18. Delivery of miRNAs: major obstacles and nanotechnology
The main hurdles associated with the nano-carriers are that the
encapsulation efciency is very low because they have a high afnity for
water, which nally leads to the diffusion of microRNA into the water
when the methods such as emulsion-based or precipitation based are
used. Another obstacle is that when the nanoparticles reach into the
blood, they surround the blood plasma protein; hence, if any particular
ligand is conjugated with the nanoparticle, it gets masked (Cun et al.,
2011). Therefore resulting in non-specic uptake and stability. Many
Table 3
Application and therapeutic effect of nanoparticles for delivering microRNA and
drugs in Breast cancer.
NPs miRNAs Application Therapeutic
effect
Stage Reference
Gold miR-145 Breast cancer miR-145
expression
recovery
In
vitro
Ekin et al.,
2014
HA-
CS
miR-34a and
doxorubicin
Triple
negative
breast cancer
Increased cell
sensitization
to DOX
In
vitro
Wang et al.,
2016; S.
Wang et al.
(2016b)
PEI miR-145 Metastatic
breast cancer
Reduced cell
proliferation
in vivo
In
vitro.
Lee et al.
(2013)
M. Banerjee and V. Devi Rajeswari
Critical Reviews in Oncology / Hematology 182 (2023) 103901
15
have proven that microRNA plays an essential role in cancer, but
translation into clinical application is still challenging. The challenges
faced are poor systemic stability, rapid clearance, and lack of efcient
delivery. The crucial challenge is the half-life of the oligonucleotides.
Their blood has only a few minutes of half-life (R et al., 2009). The
Kidney also becomes a hurdle as it clears the oligonucleotides from the
body through renal clearance. The liver also takes up these oligonucle-
otides for approval. Another reticuloendothelial with kuffer cells located
in the liver and the macrophages of the spleen eliminates these oligo-
nucleotides (Esposito et al., 2014; SK et al., 2012; Hsu et al., 2013).
Nucleases degrade the phagosome resulting from Phagocytosis of the
oligonucleotide integrated with a lysosome. As nuclease activity de-
stroys them, it is better to target them toward the cancer cells. (SK et al.,
2012) Nano-carriers mediated oligonucleotides can easily cross endo-
thelial cells and reach the tumor’s interstitial space. Therefore, directly
if the oligonucleotides are transported into the cytoplasm for translation
using a nano-carrier, they can escape the endosomal degradation. (R
et al., 2009) The problem associated with toxicity can be dealt with
using cationic polymers (SK et al., 2012). Other low molecular weight
PEI polymers are also considered efcient as they have less toxicity than
other transfection agents (Thomas et al., 2012). The PEI- based transport
system also has beneciary factors that it has rapid uptake and release of
nucleic acid inside the cell through the endocytic mechanism. Schade
et al. (2013) also showed how PEI combined with magnetic nano-
particles or quantum dots shows much more enhanced application (Park
et al., 2015). This PEI system also has an issue with biodegradability;
therefore, a much new version of the PEI-based delivery system is
required. Liposomes have the same resemblance to the cell membrane.
And tend to pass through easily. They are also biodegradable and
biocompatible. Therefore, they can be used as a delivery agent. The
problem with liposomes is that they have low specicity, which can also
be overcome by surface modication. Polymeric micelles are also an
option, as they are highly soluble in water (Bozzuto and Molinari, 2015).
19. Conclusion
TNBC is the most lethal since it exhibits the most aggressive form of
metastasis and has limited therapeutic options. The Wnt pathways are
crucial in TNBC because they affect the tumor’s growth and spread,
which can lead to lung or brain cancer. Wnt pathway is also the reason
behind anticancer drug resistance. Therefore, targeting Wnt signaling
can prevent the problem associated with current chemotherapy. Cat-
enin, as well as the molecules and co-receptors linked with Wnt
signaling, play a crucial role. As of yet, there is no targeted therapy for
Wnt signaling. As a result, a successful cure for TNBC based on the wnt
signaling pathway is expected. Wnt/βcatenin signaling is regulated by
miRNAs, which target transcription factors and play a critical role in wnt
control. microRNA can operate as a tumor suppressor or oncogene in
some cases; it could be employed as a new therapeutic method to treat
TNBC by altering Wnt signaling. This could pave the way for a victory
against TNBC cancer. Delivering microRNA to the target tissues is a
signicant challenge affecting its clinical use. The toxicity and immu-
nogenicity associated with providing agents such as viral vectors are
also substantial concerns. So, the many experiments by scientists have
led to the discovery of many nanoparticles with less toxicity and
biodegradability. Nanoparticles have made their cellular uptake easier,
as well as their availability at the tumor site. Overall, we can conclude
that conjugated nanoparticles with microRNA targeting the wnt
signaling can be a novel approach, as nanoparticles can precisely target
the microRNA to specic receptors. Many positive outcomes have been
noticed while treating other cancer targeting the wnt signaling by the
conjugated micro-RNA. Wnt signaling can be used as a biomarker. The
molecular and biochemical facts related to the Wnt signaling in the
TNBC can become more apparent in the future.
Ethical Approval and Consent to participate
Not applicable.
Funding
This research received no specic grant from the public, commercial,
or not-for-prot funding agencies.
Consent for Publication
Given by the authors and the institute.
Competing interests
The author solely contributed to this article, with No competing
interest.
Availability of data and materials
Not applicable.
Acknowledgments
We are grateful to the Vellore Institute of Technology for providing
us with all facilities required for the completion of the review.
Conict of Interest
The author declares that there was no conict of Interest.
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Ms. Manosi Banerjee is a Ph.D. scholar who is enrolled in her 2nd year of Ph.D. in the
department of the School of Bioscience and Technology at Vellore Institute of Technology,
India. She is working under the guidance of Dr. Devi Rajeswari. She has experience
working with Biolms, and antibiotic-resistance, animal models including Drosophila. She
M. Banerjee and V. Devi Rajeswari
Critical Reviews in Oncology / Hematology 182 (2023) 103901
22
has experience with Cloning and Molecular Techniques and also with proteins. She is
mainly interested in Cancer Biology. She is currently working on breast cancer. She has a
keen interest in the eld of molecular biology, biochemistry, and developing new nano-
drugs. She has published 5 publications including 2 research papers and 4 Review papers
as the co-author.
Dr. V Devi Rajeswari is currently working as an Associate Professor in the Department of
the School of Bioscience and Technology at Vellore Institute of Technology. Her Ph.D. was
based on Protein extraction and purication. She has more than 15 years of experience
with drug delivery (Nanoparticles) and is working in the eld of Diabetes and cancer
Biology. She has experience working with breast cancer. She has published more than 70
papers with an H index of 11. She has explored genes in the eld of diabetes and cancer.
She mainly focuses on the molecular mechanism associated with the disease. She has a skill
of working with animal models and all the technical skills required for cell culture and
Biochemistry. She has a keen interest to explore novel research.
M. Banerjee and V. Devi Rajeswari
