Breast cancer (BC) had 2.3 million new cases and
670,000 deaths recorded in 2022 (1). Moreover, projections indicate that
by 2050, new cases will increase by 38%, and deaths will increase
by 68% (1). It is characterized
by high heterogeneity, strong tendency for metastasis and
resistance to treatment (2,3).
The numerous types of cell that constitute the tumor
microenvironment (TME) are not static bystanders within the tumor
but are key drivers of disease progression. These cells secrete and
express key regulatory factors, such as vascular endothelial growth
factor A (VEGFA), transforming growth factor β (TGF-β), matrix
metallopeptidase-9 (MMP-9), C-C motif chemokine ligand-22 and
interleukin-10 (IL-10), which modulate the TME composition, thereby
promoting the invasive progression of tumors, malignancy and
metastasis (4). As the TME
contains specific immune and stromal cell populations with notable
prognostic value, its key role in tumor development is gradually
gaining widespread recognition, making it an emerging field of
research with therapeutic potential (5-7).
As a highly conserved signaling pathway, the Wnt
signaling network serves a key role in core physiological
processes, such as cell proliferation, differentiation, apoptosis,
migration, invasion and maintenance of cellular homeostasis
(8-10). Increasing evidence has revealed
that the abnormal regulation of the Wnt signaling pathway is
related to the occurrence and progression of BC (11,12). In more than half of BC cases, the
tumor cell nucleus has abnormally high β-catenin expression
(13). β-catenin, as a crucial
activation 'hub' in the Wnt signaling pathway and a key
transcriptional driving force in the epithelial-mesenchymal
transition (EMT) process, is associated with the histological
grade, clinical staging and lymph node metastasis and Ki-67
proliferation status of patients with BC, providing a novel
perspective for understanding the pathogenesis and prognostic
mechanisms of BC (14,15). Wnt signaling and the BC TME
exhibit a complex and multifactorial interactive dynamic
bidirectional association. Components of the TME affect the Wnt
signaling pathway within tumor cells, and abnormalities in Wnt
signaling in these cells drive changes in TME components (16-18). For example, abnormal activation of
Wnt signaling can help tumor cells in the TME evade immune system
surveillance, effectively hindering the infiltration process of T
cells, thereby mediating immune tolerance. Furthermore, in the BC
TME, the Wnt signaling pathway is not isolated but exhibits
crosstalk with other key signaling pathways (19). These signaling pathways are
coordinated, jointly regulating the dissemination and metastasis of
tumors, as well as resistance to traditional treatment methods,
revealing the complexity and diversity of BC pathogenesis (20-22).
The present review delves into the complex and
intricate mechanisms of the interaction between the Wnt signaling
pathway and TME in BC, including the functional roles of key
components and their secreted factors in the TME, unique properties
of physical influencing factors, associations with BC-related genes
and intrinsic mechanisms of interactions between cell signaling
pathways. The present review further explores the therapeutic
potential of modulating the Wnt signaling pathway within the BC TME
and its clinical implications, thereby providing new insight for BC
treatment strategies.
Under physiological conditions, the Wnt signaling
system acts as a core regulator of cellular functions through the
canonical Wnt/β-catenin signaling, non-canonical Wnt/planar cell
polarity (PCP) and Wnt-Ca2+ signaling pathways to ensure
the balance of organismal growth, development and homeostasis.
However, when key components of this network undergo mutation,
epigenetic modification or crosstalk with other signaling networks,
they trigger abnormal activation of the Wnt signaling cascade and
its downstream genes (23).
Abnormal activation of Wnt signaling is associated with accelerated
tumor proliferation, extended survival time, enhanced invasiveness
and the maintenance of cancer stem cell (SC) characteristics
(24,25). The canonical Wnt pathway promotes
proliferation by upregulating cyclin D1, enhances anti-apoptotic
capacity through B cell lymphoma-extra large and maintains cancer
SC properties. The non-canonical pathway regulates disruption of
cell polarity and metastasis via ras-related C3 botulinum toxin
substrate guanosine triphosphatases and c-Jun N-terminal kinase
(JNK) signaling (26).
Simultaneously, Wnt signaling combats ferroptosis by activating
glutathione peroxidase 4, while mediating tissue pyroptosis and EMT
via the NOD-like receptor protein 3 inflammasome (27-29). Numerous studies have explored the
diverse mechanisms of Wnt signaling activation in the occurrence
and development of cancer (23,30-32) (Fig.
1).
The canonical Wnt/β-catenin pathway is activated by
a cascade of tightly controlled steps. Initially, the Wnt ligand
forms a complex with the frizzled receptor and low-density
lipoprotein receptor-related protein 5 and 6 (LRP5/6) co-receptors,
triggering signaling. This interaction activates dishevelled (DVL),
a membrane-associated protein, which subsequently obstructs the
β-catenin degradation complex, composed of axis inhibition protein
(Axin), glycogen synthase kinase-3β (GSK-3β) and adenomatous
polyposis coli, preventing the breakdown of β-catenin.
Consequently, β-catenin accumulates in the cytoplasm before being
translocated to the nucleus. Upon binding to T cell factor/lymphoid
enhancer-binding factor (TCF/LEF) transcription factors, it induces
the activation of downstream genes. Through the activation of
downstream genes, the Wnt/β-catenin signaling pathway serves a
critical role in regulating cellular functions, such as
proliferation, differentiation, migration and apoptosis (33). Within this pathway, a negative
feedback mechanism maintains signaling equilibrium, preventing both
excessive and insufficient activation, thus decreasing the risk of
pathological conditions, such as cancer (Fig. 2) (34).
BC progression is a multifactorial process in which
the TME serves a key role. The BC TME is a diverse cellular
ecosystem that includes malignant cells, immune cell populations
and stromal tissue. These components and the factors they release
interact with the Wnt signaling pathway, collectively driving tumor
proliferation, invasion and metastasis, which are a series of
malignant events (17,37). Additionally, physical factors,
such as mechanical stress, hypoxia and acidification in tumor
regions regulate the Wnt signaling pathway and affect the
occurrence and trajectory of BC development. Analysis of the key
elements within the TME that regulate Wnt signaling provides a
theoretical foundation for uncovering the molecular mechanisms of
BC pathogenesis and developing targeted therapeutic drugs (Fig. 3).
TAMs serve a central role in innate and adaptive
immune responses because of their functional diversity and
adaptability. In the complex pathological mechanisms of BC, a
bidirectional interaction exists between Wnt signaling and TAMs,
particularly M2-type TAMs. Wnt signaling drives the polarization of
TAMs toward the M2 phenotype, which promotes the formation of an
immunosuppressive TME, thereby supporting the growth, invasion and
angiogenesis of BC and accelerating the survival and spread of
tumor cells. Inhibiting the Wnt signaling pathway through the use
of β-catenin inhibitors is an effective avenue to block M2
polarization, decreasing the expression levels of M2 markers and
thereby reversing the tumor-promoting effects of TAMs (38,39). Additionally, M2-type TAMs serve
another key role by secreting VEGFA, which activates the
neuropilin-1 (NRP-1)/GTPase-activating protein and VPS9
domain-containing protein 1/Wnt/β-catenin signaling cascade in
triple-negative BC (TNBC) cells, enhancing the self-renewal ability
and metastatic potential of tumor cells (17). Moreover, TAMs serve a critical
role in regulating the activation state of the Wnt signaling
pathway. CD68+ and M2-polarized CD163+ TAMs
release Wnt5a, a signaling molecule that triggers Wnt signaling
activity in malignant and stromal cells, forming a cycle that
continuously drives tumor progression (40-43). Due to the potential of Wnt
signaling to regulate the M2 polarization of TAMs and the
activation of Wnt signaling pathways by factors secreted by M2-type
TAMs, the Wnt-TAM axis may be a therapeutic target in BC.
T lymphocytes are key elements of adaptive immune
responses, and their dysfunction is associated with tumor
progression and the formation of immune escape mechanisms (44,45). Research has revealed the impact of
the Wnt/β-catenin signaling pathway on T cell function, which
reshapes the immune response potential of T cells by regulating the
expression of immune checkpoints, cytokine synthesis and T cell
differentiation status (46).
Specifically, the activation of the Wnt/β-catenin signaling pathway
upregulates immune checkpoint markers on the surface of
CD8+ T cells, such as programmed death receptor-1 and
cytotoxic T lymphocyte-associated protein 4 (CTLA-4) (47-49). This upregulation pushes T cells
toward exhaustion and promotes the formation of an
immunosuppressive microenvironment, facilitating tumor progression
(50). In the immune regulatory
network of BC, DVL2 is a key hub of the Wnt signaling cascade that
controls the expression pattern of Wnt target genes in
HER2+ BC cells by regulating the transcriptional
activity of genes related to immune function and T cell survival
(51). Moreover, the loss of B
cell lymphoma 9, a key transcriptional coactivator of β-catenin,
can effectively weaken abnormal Wnt/β-catenin signaling, thereby
enhancing T cell-mediated tumor immunogenicity, offering potential
for BC immunotherapy (52). In
CD8+ T cells, Wnt signaling inhibits the differentiation
of these cells into effector T cells (TEFFs). This mechanism not
only maintains the self-renewal potential of CD8+ T
cells, but also affects the differentiation fate of T cell
progenitors, contributing to the diversity and complexity of T cell
function (53). Future research
should investigate the interaction network between different T cell
subtypes, their secreted cytokines and Wnt signaling components to
provide more precise strategies for BC immunotherapy.
As regulators of immune homeostasis, Tregs play key
roles in regulating immune response and preventing excessive
autoimmunity (54). Previous
studies have analyzed the mechanisms of the Wnt signaling pathway
and related molecules, including Wnt ligands, forkhead box P3
(FoxP3), poly(C)-binding protein 1 (PCBP1), and dickkopf-related
protein 3 (DKK3) in the TME of Tregs (55-58). Specifically, Wnt ligands activate
β-catenin signaling in dendritic cells, driving the balance between
TEFF and Tregs (55). However,
when β-catenin signaling is overly active, this balance is
disrupted, leading to impaired dendritic cell recruitment,
inhibition of CD8+ T cells, and proliferation of Tregs,
which suppress the antitumor immune response (16,56). By inducing FoxP3 expression, the
Wnt/β-catenin signaling pathway promotes the activation and
differentiation of Tregs, triggering the release of
immunosuppressive factors, such as TGF-β and IL-10. This
facilitates tumor growth and immune evasion (56,59,60). In BC, the role of PCBP1 in
modulating Wnt signaling is key for stimulating adaptive antitumor
immune responses, and its decreased expression is associated with
the imbalance of immune cell populations within tumors, which
promotes the expansion of Tregs and subsequently inhibits the
activation of antitumor immune responses (57). Additionally, DKK3 secreted by
tumors may promote the reprogramming of CD4+ cells into
Tregs by blocking the Wnt signaling pathway, thereby supporting the
survival and spread of tumor cells (56,58). Thus, the association between
Wnt/β-catenin signaling and Tregs in the BC TME may provide a
theoretical foundation for developing targeted treatment strategies
aimed at enhancing antitumor immune responses and improving
clinical outcomes.
CAFs, a highly plastic and heterogeneous stromal
cell population in the BC TME, not only maintain the structural
framework and mechanical stability of tissue but also regulate
biochemical signal transduction processes (61,62). In response to Wnt/β-catenin
signaling, CAFs undergo transformation under the induction of Wnt
proteins, secreting a range of bioactive molecules and generating
exosomes, which facilitate tumor growth and invasion (63,64). There is an association between the
origin of CAFs in BC and Wnt proteins. For example, Wnt7a
transforms quiescent fibroblasts into α-smooth muscle
actin-positive CAFs by binding to TGF-β receptors, thereby
activating their potent tumor-promoting potential (62). Tumor-derived Wnt3a promotes
conversion of adipocytes to CAFs by activating the Wnt/β-catenin
signaling pathway (62,65). Further research has revealed that
CAFs, as a key source of Wnt ligands, actively promote BC
progression by releasing paracrine signals (65,66). These signals maintain tumor
stemness, stimulate the growth of the primary tumor and accelerate
the metastatic colonization process (63,64). For example, Wnt3a activation
enhances the synthesis of key matrix proteins, such as fibronectin
and type I collagen, which further induces synthesis of MMP-9 in BC
cells, thereby enhancing their migration and invasion capability
(65,67,68). CAF-derived exosomes carrying CD81
serve a key role in stimulating BC cell motility due to activation
of the Wnt/PCP signaling pathway. Wnt10b contained within the
exosomes triggers a self-reinforcing cycle by activating the
Wnt/β-catenin pathway, promoting progression and widespread
dissemination of tumors (66,69). Therefore, the interaction between
CAFs and the Wnt signaling pathway underlies the progression of BC
and may provide a basis for development of innovative treatment
strategies.
MSCs have garnered attention for their potential to
differentiate into various cell types, such as adipocytes,
osteoblasts and chondrocytes, which affect tumor angiogenesis,
immune modulation and responses to antitumor therapy (70-72). In regulating interactions with BC
cells, the Wnt signaling pathway serves as a key factor in driving
tumor growth and bone metastasis, while also inhibiting tumor
progression through diverse mechanisms (73). Specifically, the Wnt signaling
pathway connects MSCs with cancer cells, enhancing the
pro-tumorigenic properties of MSCs by inducing their
differentiation into CAFs (74).
Wnt5a released by BC cells triggers the secretion of IL-6 and
monocyte chemoattractant protein-1, which enhances the
phagocytic-like activity of MSCs and accelerates tumor
dissemination. In in vitro models of BC bone metastasis, the
Wnt/β-catenin pathway regulates osteogenic activity in a bone
microenvironment composed of human MSCs, promoting the progression
of BC bone metastasis (75,76). The functions of MSCs are not
limited solely to promoting tumorigenesis; they also have the
ability to inhibit tumor growth (77-79). MSCs effectively limit tumor
progression through a number of biological mechanisms, including
weakening Wnt and AKT signaling, blocking angiogenesis, stimulating
the recruitment of inflammatory cells and inducing cell cycle
arrest and apoptosis (77-82).
In Michigan Cancer Foundation-7 cells, DKK1 derived from MSCs
successfully inhibits tumor cell proliferation by downregulating
β-catenin signaling (65,77). Additionally, in controlled
experimental settings, chondrogenic membrane-derived MSCs inhibit
the proliferation of BC cells, an effect mediated by the regulation
of the Wnt/β-catenin signaling cascade. These findings revealed the
dual nature of MSCs in BC, emphasizing their potential in both
promoting and inhibiting tumor progression through different
signaling pathways. Future studies should clarify the specific
functions and pathways of MSCs in BC.
VEGF is a key factor in regulating angiogenesis,
tumor progression and metastatic spread and promotes the generation
of a tumor immune-suppressive environment (83,84). Wnt signaling influences
endothelial cells and paracrine signaling, further regulating
vascular smooth muscle and vascular network structure (85,86). In BC, the canonical Wnt pathway
not only drives the transcription of VEGF but also interacts with
VEGF and its key receptor NRP-1, whereas the non-canonical Wnt
pathway collaborates with VEGF to affect angiogenesis and cancer
progression. Activation of the Wnt/β-catenin pathway can directly
lead to the transcription of multiple target genes, including VEGF,
by stabilizing β-catenin and promoting its transfer to the nucleus,
thereby driving angiogenesis (87). In the formation of BCSCs and the
induction of tubular angiogenic structures, the binding of VEGFA to
its receptor NRP-1 serves a key role. In the VEGFA/NRP-1 signaling
axis, the Wnt/β-catenin signaling pathway acts as a key downstream
effector; its transmission is triggered by the activation of VEGFA,
thereby facilitating persistence of CSCs (88,89). This cascade enhances the invasive
potential of tumors and accelerates the malignant transformation of
breast tissue. In addition, the non-canonical Wnt pathway often
works together with VEGF, regulating key events in tumor
angiogenesis, such as endothelial cell movement, increased vascular
permeability and extracellular matrix remodeling (90,91). Given the key role of Wnt signaling
in BC angiogenesis, precise therapeutic strategies targeting this
pathway may provide novel avenues for overcoming resistance to
traditional anti-angiogenic therapy, thus holding clinical
translational potential.
Exosomes, as nanoscale vesicles for intercellular
communication, play a key role in tumor progression and acquisition
of therapeutic resistance within the TME (37,92-96). In BC, the Wnt signaling pathway
influences the evolution of tumors, chemoresistance and the
development of resistance reversal strategies by regulating the
content of microRNAs (miRNAs or miRs) in different exosomes
(97,98). Specifically, under the action of
the Wnt signaling pathway, BC cells decrease levels of miR-7-5p in
exosomes, thereby enhancing their migration and invasion capability
and releasing miR-454 to maintain the self-renewal potential of
CSCs (99,100). The roles of exosomal miRNAs in
BC progression vary. Among them, exosomal miR-10527-5p can block
the Wnt/β-catenin signaling pathway to inhibit cancer cell
migration and invasion, whereas miR-7-5p from exosomes derived from
less invasive BC cells inhibits metastasis by targeting the
receptor-like tyrosine kinase gene and the non-canonical Wnt
pathway (99,100). Conversely, upregulated
miR-142-3p expression activates the Wnt pathway and induces miR-150
production, thereby promoting the over-proliferation of BC cells
(101). Exosomes serve a central
role in chemoresistance. Chemotherapy-induced exosomes activate the
Wnt/β-catenin pathway by targeting DKK3 and Notch signaling pathway
inhibitor protein numb homolog, inducing resistance; exosomes
released by paclitaxel-resistant BC cells carry miR-187-5p that
regulates ATP-binding cassette subfamily D member 2 and the
Wnt/β-catenin pathway, affecting proliferation. Exosomes
transported from adipose-derived MSCs transfer miR-1236, which
decreases resistance to cisplatin by inhibiting solute carrier
family 9 member A1 activity and Wnt/β-catenin signaling (101). These findings not only reveal
the dual role of exosomes in BC progression, but also provide a
basis for exploring resistance reversal strategies in BC.
Mechanical stress resulting from the integrated
action of multidimensional factors, such as tissue topography,
matrix stiffness, physical stretching, shear stress and
compression, is closely related to the initiation, development and
dissemination of cancer (102,103). Mechanical stress regulates BC
progression by affecting the response of adipocytes, SCs, cancer
cells and fibroblasts to the Wnt signaling pathway. For example,
shear stress can downregulate the expression of SC marker
molecules, thereby blocking the Wnt/β-catenin pathway, increasing
cellular stiffness and inducing the differentiation of cancer cells
toward a mature state (104).
Adipocytes, an important component of breast tissue, undergo
dedifferentiation transformation via the mechanosensitive response
mechanism of the Wnt/β-catenin pathway when subjected to physical
compression, forming compression-induced dedifferentiated
adipocytes (CiDAs) (105). CiDAs
accelerate myofibroblastosis within the TME, facilitating BC cell
proliferation (105). Matrix
rigidity serves a key role in regulating the invasive potential of
breast tumor cells at the primary site of disease (106-108). The combination of matrix
rigidity and matrix-secreted factors stimulates Gli family zinc
finger protein 2 and parathyroid hormone-related protein through
Wnt signaling in osteolytic breast cancer cells, driving
tumor-induced osteolysis (109).
Intervention strategies targeting physical factors and the Wnt
signaling pathway may provide an effective therapeutic approach to
delay tumor metastasis (103,109).
Hypoxia, a constant and heterogeneous characteristic
of the TME, is pervasive in most types of solid tumor owing to the
abnormally high expression of hypoxia-inducible factors (HIF) under
low-oxygen conditions (110,111). In the hypoxic microenvironment
of BC, HIF regulates the Wnt signaling pathway and stability of
β-catenin while inducing upregulation of runt-related transcription
factor 2 (RUNX2) and inhibiting the activation of GSK3,
facilitating aggressive progression of tumors and the enhancement
of cancer cell invasiveness. Specifically, HIF-1α stabilizes the
structure of β-catenin and enhances its transcriptional activity;
on the other hand, it upregulates the expression of Wnt ligands and
receptors, thereby transcriptionally activating Wnt1-inducible
signaling pathway protein 3. This activates the Wnt pathway,
facilitating tumor growth, metastasis and angiogenesis (112). Concurrently, HIF-2α reprograms
normal cells into a SC-like phenotype by activating the Wnt
signaling pathway in BC cells and induces chemotherapy resistance
(113). This not only drives
metabolic reprogramming and maintains stemness of BC cells but also
enhances glycolysis and glutaminolysis through the Wnt/β-catenin
pathway, ensuring the survival of cancer cells under extreme
hypoxic conditions (114-120).
Hypoxia-induced RUNX2 upregulates RNA binding motif protein
5-antisense RNA 1, preventing the degradation of β-catenin and
promoting the formation of β-catenin-TCF4 transcription complex,
thereby amplifying the effect of the Wnt/β-catenin pathway and
accelerating tumor progression (121). Hypoxic conditions inhibit the
activation of GSK3, decreasing the phosphorylation and subsequent
degradation of β-catenin, further activating the Wnt/β-catenin
pathway, leading to increased expression of snail family
transcriptional repressor 1, and enhancing the invasiveness of
cancer cells (122). These
findings not only reveal the key role of hypoxia in tumor
progression but also provide perspective for the development of
innovative therapy.
A common characteristic of solid tumors is the
acidic metabolic environment, which not only promotes the
proliferation of tumor cells, but also serves a key role in
resistance to radiotherapy and chemotherapy (123). The acidic TME is primarily
shaped by hydrogen ions released from the dissociation of lactate
and carbonic acid. Lactate originates from the anaerobic glycolysis
of tumor cells, whereas carbonic acid is generated by the reaction
of CO2 with H2O catalyzed by carbonic
anhydrase (CA) (123). In BC,
abnormal regulation of CA exacerbates this acidification, further
disrupting the internal pH balance of tumors (124). Intracellular acidification
triggers the activation of the unfolded protein response and ATP
depletion, thereby inhibiting Wnt signaling activity (125). Drugs that induce intracellular
acidification (such as mitochondrial complex I) effectively
suppress the Wnt signaling pathway, decrease the expression of
SRY-box transcription factor 4 and inhibit SC characteristics and
activity of BC cells (125).
These findings not only reveal the potential of targeting the Wnt
pathway in BC treatment but also provide perspective on strategies
that exploit the acidic TME. Therefore, modulating the pH of the
TME may serve as an innovative adjuvant therapy, laying a
foundation for tumor treatment.
In recent years, with the continuous advancement of
oncology research, the association between BC-related genes and the
Wnt signaling pathway has become a research hotspot in this field
(126-128). BC-associated genes, such as
BRCA1, BRCA2 and tumor protein P53 (TP53) are associated with the
Wnt signaling pathway and serve key roles in maintaining normal
physiological function, genomic stability and cell fate
determination.
BRCA1 and BRCA2. BRCA genes, mainly BRCA1 and BRCA2,
are closely associated with the risk of hereditary BC (129,130). They effectively inhibit
excessive cell proliferation and maintain genomic stability by
repairing double-stranded DNA breaks (131). In germline BRCA1 mutation
carriers, the microenvironment harboring heterozygous BRCA1
mutations may promote BC development by creating a tumor-promoting
niche, particularly by affecting the stromal cells residing in the
TME (132,133). Wu et al (134) reported that in basal-like BC,
the Wnt effector Slug epigenetically suppresses BRCA1, resulting in
a negative association between Wnt signaling and BRCA1 expression.
Furthermore, Wu et al (134) indicated that canonical Wnt
signaling drives cancer cell EMT and tissue invasion by modulating
Slug activity, inhibiting the function of BRCA1 and BRCA2 and
rendering breast epithelial cells more vulnerable to
etoposide-mediated DNA damage. Li et al (135) revealed that BRCA1 deficiency may
increase the sensitivity of the active form of β-catenin protein to
H2O2, thereby decreasing its expression. To
the best of our knowledge, however, research on the association
between BRCA genes and the Wnt signaling pathway remains limited,
and more mechanistic studies are needed (135).
TP53 gene mutations serve a key role in BC.
Transcription factor p53, encoded by TP53, serves a crucial role in
regulating a series of cellular activities, including cell cycle
arrest, apoptosis, metabolic regulation, DNA repair and cellular
senescence (136-138). Abnormal activation of the Wnt
signaling pathway effectively suppresses TP53 activity, thereby
facilitating survival of tumor cells and enhancing their resistance
to apoptosis (139). In BC
cells, the absence of TP53 promotes the release of key Wnt factors,
such as Wnt1, Wnt6 and Wnt7a, but also stimulates TAMs to produce
IL-1β, a key inflammatory mediator, through the binding of these
factors with frizzled class receptor 7 (FZD7) and FZD9 receptors on
the surface of TAMs (140).
Moreover, in TP53-deficient basal-like BC tumors, activity of the
Wnt signaling pathway is enhanced and is often accompanied by the
expression of the non-canonical Wnt signaling mediator receptor
tyrosine kinase-like orphan receptor 2 (Ror2). The existence of
Ror2 as an alternative Wnt receptor enhances the diversity of Wnt
signaling and supports Wnt/β-catenin-independent signaling
functions in TP53-deficient model (141). Therefore, the combined
inhibition of TP53 and the Wnt signaling pathway may provide
effective therapeutic options for patients with BC.
Somatic genomic aberrations in breast tumors disrupt
key signaling networks that regulate cell division, survival and
differentiation, highlighting numerous potential biomarkers and
therapeutic targets (142).
Previous studies have demonstrated crosstalk between the Wnt
signaling network and key pathways within the TME, including TGF-β,
phosphatidylinositol-3 kinase (PI3K)/Akt, fibroblast growth factor
(FGF) and Hedgehog signaling (37,143,144). These signaling networks not only
control tumor cell proliferation and migration, but also serve
indispensable roles in immune evasion, metabolic reprogramming and
therapeutic resistance, which are critical biological processes
(145). The association between
the Wnt signaling pathway and other core pathways, as well as the
underlying biological mechanisms, may serve as potential
therapeutic strategies and biomarkers (Fig. 4).
The Wnt and TGF-β signaling pathways, as
evolutionarily conserved regulatory mechanisms, serve crucial roles
in embryonic differentiation, tissue homeostasis and pathological
processes. Abnormal activation is closely associated with BC
progression, increased potential for metastasis and poor clinical
prognosis (146,147). The mechanisms by which these
pathways influence BC primarily involve driving EMT, inducing
immune evasion and maintaining BC cell stemness (148). EMT, as a key mechanism of tumor
metastasis, is regulated by the Wnt and TGF-β signaling pathways.
TGF-β, acting as a catalyst for EMT, can prompt epithelial cells to
transition into invasive mesenchymal phenotypes (149). Concurrently, the Wnt pathway,
particularly its β-catenin-activated form, promotes EMT. These two
pathways collectively regulate gene expression networks associated
with EMT through interactions between β-catenin and SMAD proteins,
thereby accelerating the invasion and migration of BC cells
(149). In addition to
regulation of EMT, the crosstalk between the Wnt and TGF-β
signaling pathways amplifies their individual effects in promoting
immune evasion. TGF-β signaling activates immune escape mechanisms,
while Wnt signaling is involved in immune modulation, especially in
promoting immune tolerance (32,150). The maintenance of BCSCs is a
component of the functional intersection of Wnt and TGF-β pathways,
which are key for tumor development, metastasis and the emergence
of therapeutic resistance. The Wnt pathway drives the self-renewal
of BCSCs via β-catenin-mediated transcriptional activation, whereas
TGF-β enhances the maintenance of BCSCs by promoting stemness
(151). More specifically,
non-canonical Wnt signaling, by maintaining CSCs in a quiescent
state in association with TGF-β signaling, enhances the EMT
process, thereby promoting the maintenance and expansion of CSCs
(151). Interactions between
these pathways provide valuable insight for the development of
innovative therapeutic interventions. Compared with the inhibition
of a single pathway, targeting both Wnt and TGF-β pathways
simultaneously provides a more efficient approach to improving the
outcomes of BC treatment (152,153).
The PI3K/Akt pathway plays a pivotal role in
regulating core cellular activities, such as proliferation,
division, metabolic adaptation, survival and angiogenesis (154,155). The PI3K/Akt and Wnt pathways are
associated with tumor biological behaviors through regulating CSC
self-renewal, accelerating EMT and metastasis and affecting
angiogenesis, thus facilitating progression of BC. In BC, a key
factor in the combined action of the Wnt and PI3K/Akt signaling
pathways to promote CSC self-renewal is the interaction between
β-catenin and the PI3K regulatory subunit p85α, which enhances the
catalytic activity of PI3K, thereby triggering the phosphorylation
and activation of Akt (156,157). Further research has shown that
the PI3K/Akt pathway intersects with the canonical Wnt signaling
cascade under the regulation of GSK3β, where Akt phosphorylates and
inhibits GSK3β, amplifying the efficiency of Wnt signal
transduction and further promoting the self-renewal of CSCs
(158-160). In terms of promoting EMT and
metastasis, Siddharth et al (161) revealed the overexpression of
nectin-4 drives Wnt/β-catenin signaling through the PI3K/Akt axis,
thereby enhancing the EMT process and promoting metastasis.
Simultaneously, the PI3K/Akt signal phosphorylates and activates
β-catenin; this upregulates the expression spectrum of genes
associated with EMT and enhances its interaction with TCF/LEF
transcription factors, thus advancing the EMT process (162). 3,5,4′-trimethoxystilbene can
affect E-cadherin levels and nuclear localization of β-catenin by
regulating the PI3K/Akt signaling axis and GSK3β, thereby reversing
EMT in BC cells (163). In
addition, the role of Wnt3a and the PI3K/Akt pathway in
angiogenesis has attracted increasing attention (164). Thymoquinone, as an effective
inhibitor, simultaneously impairs the normal function of PI3K and
Wnt3a signaling pathways, thereby inhibiting angiogenesis (164). Arqués et al (165) reported that the combined use of
the PI3K inhibitor BKM120 and the Wnt signaling inhibitor LGK974
can decrease tumor progression and metastasis in BC. These findings
provide a theoretical and experimental basis for the development of
targeted therapeutic strategies for the PI3K/Akt and Wnt signaling
pathways and the formulation of personalized treatment plans.
FGFs are involved in controlling a broad range of
cellular functions, including SC survival, proliferation,
programmed cell death inhibition, drug resistance and angiogenesis
(166,167). The FGF signaling pathway
interacts with the Wnt pathway and regulates the transcriptional
activity of target genes. Members of the FGF family activate the
Wnt pathway through various mechanisms, such as inducing β-catenin
modification and promoting the phosphorylation of low-density LRP6,
and these pathways exhibit synergistic oncogenic effects in mouse
mammary tumor virus (MMTV)-induced tumors. FGF family members FGF18
and FGF20 promote Wnt pathway activation via
β-catenin-TCF/LEF-dependent transcription (168,169). Activation of FGF receptors
induces tyrosine phosphorylation-mediated modification of
β-catenin, leading to the detachment of β-catenin from adherens
junctions and a decrease in its N-terminal serine/threonine
phosphorylation levels. By blocking the proteasomal degradation
pathway of β-catenin, this mechanism enhances the self-reinforcing
loop of the canonical Wnt signaling pathway (170-172). Additionally, FGF signaling
promotes the phosphorylation of LRP6 mediated by cyclin
Y/vertebrate homolog PFTK, further activating the Wnt pathway
during the G2/M transition of the cell cycle (173). The interaction between Wnt-1 and
FGF3 was initially detected in tumors induced by MMTV (174,175). FGF3, as an oncogene, triggers
the occurrence of ~40% of MMTV infection-dependent tumors with
Wnt-1. MMTV insertional mutagenesis studies have demonstrated that
simultaneous activation of Wnt and FGF signaling components is one
of the most common genetic alterations in breast tumors (176,177). Overactivation of the Wnt and FGF
signaling pathways is considered a potential molecular marker for
predicting the response of BC to next-generation eukaryotic
initiation factor 4A RNA helicase inhibitors (178). Therefore, the interaction
between Wnt and FGF signaling in the BC TME is a dynamic and
complex process that affects the behavioral patterns of tumor cells
and promotes BC progression.
The Hedgehog signaling cascade is a highly
conserved process in evolution and serves a crucial role in cell
differentiation, tissue development, homeostasis and EMT (179). Within the complex network of
tumor biology, the crosstalk between the Wnt and Hedgehog signaling
pathways primarily occurs through the transcription factor
Gli1-mediated control of secreted frizzled-related protein 1
(sFRP-1) and sonic hedgehog (Shh) expression, and Gli1 exerts a
synergistic impact with β-catenin, shaping the progression of BC.
Specifically, the key transcription factor Gli1 in the Hedgehog
pathway mediates crosstalk with the Wnt pathway by regulating the
negative regulator sFRP-1 in the Wnt signaling pathway (180). When the function of sFRP-1 is
compromised, the canonical Wnt pathway is abnormally activated,
leading to disorders in the signaling network (180). The regulatory role of Gli1 is
not limited to sFRP-1 but also involves other members of the Wnt
family, such as Wnt2b, Wnt4 and Wnt7b. Furthermore, Gli1
upregulates the expression of the secreted Hedgehog Shh, which
transmits paracrine signals to the surrounding stromal cells,
triggering biological effects. Upon receiving the Shh signal,
stromal cells upregulate the expression of forkhead box F1 (Foxf1)
and Foxf2, thereby inhibiting the production of Wnt5a in the stroma
and indirectly regulating the activity of β-catenin (181). There is an association between
nuclear Gli1 and β-catenin activity. The expression of exogenous
constitutive nuclear β-catenin can enhance the activity of Gli1
reporter genes, indicating that the sustained activation of Wnt
signaling can enhance the transcriptional efficacy of Gli (182). Arnold et al (183) reported that the co-elevation of
nuclear Gli1 and β-catenin activity is associated with the
progression of TNBC stage and poor clinical prognosis (183). Concurrent activation of the
Hedgehog and Wnt pathways is also associated with a decline in
recurrence-free and overall survival rates in patients with TNBC
(183). Thus, the synergistic
activation of the Wnt and Hedgehog pathways may serve as an
important biomarker for the progression and therapeutic response of
BC, providing avenues for optimizing clinical treatment plans and
improving the prognosis of patients with BC.
While exploring the complex mechanisms of the TME,
abnormal regulation of the Wnt signaling pathway has been
identified as a key element in tumor progression, affecting
angiogenesis, immune evasion and metastasis (184). In addition, the Wnt signaling
pathway affects the efficacy of anti-HER2 therapy, chemotherapy and
immunotherapy, influencing the success of BC treatment and patient
prognosis. For example, in HER2-overexpressing BC cells, Wnt3
overexpression activates the Wnt/β-catenin signaling pathway, which
not only leads to the transactivation of EGFR and promotes an
EMT-like transformation but may also be a key cause of trastuzumab
resistance (185,186). This signaling pathway may
regulate CD36 levels, prompting resistant mesenchymal CSCs to
transition to a treatment-sensitive epithelial state, thereby
affecting lapatinib resistance (187,188). In vitro studies by Xu
et al (189) have shown
that β-catenin expression is associated with chemoresistance in
TNBC, as β-catenin knockdown can restore the sensitivity of TNBC
cells to doxorubicin- or cisplatin-mediated cell death. Shetti
et al (190) reported
that the combination of low-dose paclitaxel and XAV939 (a Wnt
signaling inhibitor) can inhibit EMT and angiogenesis by inducing
apoptosis and suppressing Wnt signaling, demonstrating its
therapeutic potential for TNBC. Upregulation of CSC-related Wnt
signaling and activation of β-catenin signaling in PD-L1-high TNBC
suggest that selective Wnt/β-catenin inhibitors may decrease
resistance and re-sensitize TNBC to anti-PD-L1/anti-CTLA-4
monoclonal antibody immunotherapy (191-195).
Developing therapeutic strategies targeting both
the canonical and non-canonical Wnt signaling pathways is key for
advancing precision medicine and genome-based disease therapy. Wnt
pathway inhibitors, including porcupine (PORCN) and LRP5/6
inhibitors, frizzled receptor antagonists, tankyrase inhibitors and
natural compounds may be used to target the Wnt signaling pathway
in the BC TME (Fig. 5). These
inhibitors not only modulate the complex signaling network within
the TME but also suggest that precise intervention in the Wnt
pathway may provide new avenues for BC treatment.
PORCN, a member of the membranebound
O-acyltransferase family, catalyzes the palmitoylation of Wnt
ligands, a key step that allows Wnt ligands to be secreted, and
effectively activates the Wnt signaling pathway, thereby regulating
fundamental physiological functions, such as cell differentiation,
proliferation, migration and apoptosis (196-201). To intervene in the
palmitoylation of Wnt proteins within the endoplasmic reticulum,
PORCN inhibitors effectively prevent the secretion of Wnt proteins
and curb the abnormal accumulation of β-catenin to restore normal
cell proliferation and signal transduction (202,203). In a preclinical study of BC
mice, the PORCN inhibitor GNF-6231 showed strong antitumor
activity, stimulating a notable tumor response (204). Similarly, another PORCN
inhibitor, LGK974, not only blocks the secretion of Wnt proteins,
but also effectively inhibits the activation of Wnt signaling
(205). In a preclinical study
of epithelial ovarian cancer, LGK974 in combination with paclitaxel
demonstrates synergistic antitumor effects (206). In BC models induced by Wnt
signaling, such as the MMTV model, LGK974 also performs well at
doses tolerable to animals, achieving tumor regression while
decreasing the phosphorylation levels of LRP6 and the expression of
Axin2 (207,208). LGK974 has entered phase I
clinical trials, and its potential as a monotherapy in combination
with PDR001 for the treatment of Wnt signaling-driven cancer,
including TNBC, is being evaluated (207,209). The aforementioned trials aim to
assess the clinical efficacy and safety of LGK974 and to propose
innovative strategies for Wnt signal inhibition in BC treatment
(30).
LRP5/6, a key co-receptor in the Wnt signaling
pathway, plays a key role in the β-catenin-mediated canonical
signal transduction process. Alkalescel, initially recognized as an
antimicrobial potassium ionophore, inhibits phosphorylation of
LRP5/6 and promotes its degradation, thereby inhibiting BC cell
proliferation and inducing apoptosis (210). Salinomycin can downregulate
LRP5/6 expression, further decreasing the transmission of Wnt
signaling (211,212). By contrast, niclosamide acts on
LRP6 by blocking its phosphorylation and downregulating its protein
synthesis. In BC cell models, niclosamide inhibits cellular
proliferation and promotes apoptosis without affecting DVL2
expression (213,214). Research on BC cells has
confirmed that niclosamide could inhibit tumor sphere formation in
non-obese diabetes/severe combined immunodeficiency mice, promote
apoptosis and effectively curb tumor growth, providing support for
its application in CSC-directed therapy (215). Furthermore, using a mouse BC
model, Ye et al (216)
reported that niclosamide decreases tumor cell proliferation,
migration and invasion, while promoting apoptosis and decreasing
tumor weight. These findings demonstrate the mechanisms of action
of LRP5/6 inhibitors and provide insights for BC treatment
strategies.
Vantictumab is a fully human IgG2 monoclonal
antibody that selectively targets frizzled receptors and
effectively disrupts the canonical Wnt signaling pathway (217). Preclinical experiments involving
human cancer cell cultures and patient-derived BC xenograft models
have shown that vantictumab not only impedes tumor progression but
also exhibits enhanced antitumor efficacy when combined with
paclitaxel compared to monotherapy (217,218). Sequential treatment with
vantictumab and paclitaxel induces mitotic cell death, decreases
tumor proliferation and decreases CSC numbers. Vantictumab
decreases the number of CSCs and downregulates the expression of
EMT-associated genes (219).
Tankyrase regulates Axin stability and directs its
degradation through PARsylation (220). In a BC cell culture, XAV939 or
small interfering RNA-mediated tankyrase knockdown significantly
increases the expression of Axin1 and Axin2 proteins, thereby
inhibiting Wnt-induced transcriptional activity (221). Tankyrase inhibitor MSC2504877
exerts G1 phase cell cycle arrest effects in tumor cells, promotes
cellular senescence and enhances the efficacy of clinically used
CDK4/6 inhibitors, facilitating development of BC treatment
(222).
Natural products are used for the development of
anticancer drugs. The use of these naturally derived compounds and
their derivatives to modulate the TME and target the Wnt signaling
pathway is becoming a highly promising direction in BC treatment
(223-225). Phytochemicals regulate the Wnt
signaling cascade, thereby providing options for future drug
development (Table I).
BC, which poses a threat to lives and safety, has
long been a core focus of medical research and clinical practice
(226,227). The biological research system of
BC is intricate, and the multidimensional network constructed
between the Wnt signaling pathway and TME forms a cornerstone in
this field of study (228-230). The components of the TME are
associated with the Wnt signaling pathway, creating dynamic
regulatory network. Immune cells releasing cytokines to regulate
Wnt signaling, stromal components influencing signal transmission
through chemical induction and secreted molecules directly
interacting with key proteins in the pathway affect the
proliferation, migration and invasion of tumor cells, and serve a
role in promoting immune evasion, metabolic reprogramming and
enhancing therapeutic resistance (231,232).
The hallmark features of the TME, such as hypoxia,
acidity and mechanical stress, are associated with the Wnt
signaling pathway, promoting the continuous progression of tumors
(233,234). The Wnt signaling pathway
interacts with key signaling networks, such as TGF-β, PI3K/Akt, FGF
and Hedgehog, forming a highly interconnected regulatory pattern.
Therefore, single-target treatment strategies for the Wnt signaling
pathway may be insufficient to inhibit development of tumors.
Therefore, developing combination treatment plans that act on
multiple key nodes in these signaling networks is key for more
effective treatment.
Given the role of the Wnt signaling pathway in the
heterogeneous microenvironment of BC and its association with
treatment resistance, it has become a key target for identifying
novel biomarkers (14,235). By exploring the effector
molecules of the Wnt signaling pathway and the association between
Wnt signaling activity and patient prognosis, more precise
predictive biomarkers can be developed (236,237). For example, cyclin D1 is
upregulated following activation of the Wnt pathway and may promote
the proliferation of BC cells (238). Ras GTPase-activating
protein-binding protein 1 (G3BP1) induces β-catenin by inactivating
GSK-3β, thereby increasing the proliferation of BC cells. Blocking
the interaction between G3BP1 and GSK-3β inhibits cell
proliferation (239).
Platelet-activating factor, a co-factor of β-catenin, can induce
Wnt signaling, promote the proliferation of BC cells and increase
the expression levels of CSC markers (240,241). The downregulation of
autophagy-related protein 4A leads to decreased expression of
β-catenin, cyclin D1 and MYC proto-oncogene protein c-Myc, which
impacts the autophagy process and enhances the chemosensitivity of
tamoxifen in BC. Deficiency of fibrous sheath interacting protein 1
promotes autophagy, resulting in decreased Wnt/β-catenin activity
and influencing drug sensitivity in TNBC (242). Kallistatin, a tissue
kallikrein-binding protein and a unique serine proteinase
inhibitor, inhibits the proliferation, migration, invasion, and
tumor progression of BC cells by blocking the Wnt/β-catenin
signaling pathway and inducing autophagy (243). Additionally, the genetic
background of patients, such as the mutation status of BRCA1/2, may
influence Wnt signaling activity, thereby providing a basis for the
development of personalized treatment strategies.
In studies exploring the relationship between the
Wnt signaling pathway and tumor cell death, it has been confirmed
that the Wnt signaling pathway is not only closely related to the
apoptosis and autophagy processes of breast cancer cells, but also
associated with disulfidptosis, a specific type of cell death
caused by disulfide accumulation (244,245). Wnt signaling activation not only
promotes tumor cell self-renewal but also modulates serine
peptidase inhibitor, clade B, member 6B (SERPINB6B) to decrease
immune cell death and interfere with T cell-mediated tumor lysis
(246). Specifically, SERPINB6B
suppresses pyroptosis and immune recognition, thereby inhibiting
apoptosis of immunogenic cells at metastatic sites and facilitating
tumor dissemination (246).
However, knowledge gaps persist in the context of the BC TME,
particularly regarding the interaction between Wnt signaling and
other tumor cell death modalities such as disulfidptosis,
ferroptosis, autophagy and pyroptosis. Future studies should
integrate multidisciplinary approaches, including genomics,
proteomics, bioinformatics, high-throughput screening technology
and precision medicine strategies, to systematically investigate
the crosstalk between Wnt signaling and tumor cell death mechanisms
and identify novel therapeutic targets and clinically actionable
biomarkers.
Small-molecule inhibitors and natural compounds
regulate Wnt pathway activity, effectively inhibiting the
proliferation and migration of tumor cells, while accelerating
apoptosis (247). Existing
research indicates that these inhibitors and compounds may have
clinical translation and application potential in BC (49). However, despite scientific
advancements, the pace of clinical translation is slow, with most
Wnt pathway-targeting drugs in phase I clinical trials, constrained
by thorough safety validation and preliminary efficacy assessment,
and only a few advancing to phase III trials (Table II) (248-250). The clinical safety and efficacy
of Wnt-targeting small molecules and natural compounds must be
validated to confirm their therapeutic potential where toxicity
poses a barrier. For example, salinomycin carries the risk of
neurotoxicity, potentially inducing peripheral neuropathy, whereas
niclosamide is associated with dose-limiting toxicity, posing a
threat to the gastrointestinal system (251,252). Future research should focus on
enhancing the clinical safety and efficacy of these compounds,
which may be achieved through the optimization of chemical
structures or development of innovative drug delivery technology to
enhance bioavailability and reduce adverse reactions (253). This may provide more effective
and safer treatment options for patients with BC and improve
prognosis and overall quality of life.
Not applicable.
CS and RL conceived and designed the study. MS and
HZ wrote and edited the manuscript, constructed the figures and
performed the literature review. YYu, YYa and HL revised the
manuscript. FF and QW constructed figures. All the authors have
read and approved the final manuscript. Data authentication is not
applicable.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
Not applicable.
The present study was supported by the National Natural Science
Foundation of China Key Project (grant no. 82430123), National
Natural Science Foundation of China General Program (grant no.
82174222), Science and Technology Cooperation Project of the
Department of Science and Technology of the Traditional Chinese
Medicine Administration (grant no. GZY-KJS-SD-2023-023), National
Major Scientific and Technological Special Project for the
Prevention and Treatment of Cancer, Cardio-cerebrovascular,
Respiratory, and Metabolic Diseases (grant no. 2024ZD0521406) and
Shandong Province Taishan Scholar Distinguished Expert Reward
Program (grant no. tstp20221166).
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