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).

The main components of the non-canonical Wnt signaling network are the Wnt/Ca²⁺ and Wnt/PCP pathways. These signaling networks act independently of β-catenin to activate separate cellular signaling processes. Wnt proteins, including Wnt1, Wnt5a and Wnt11, activate the Wnt/Ca²⁺ signaling pathway via engagement with frizzled receptors on the cell surface. Upon binding, the G proteins are activated. These molecules activate phospholipase C, resulting in an increase in intracellular Ca²⁺ concentration. It also causes a decrease in cyclic guanosine monophosphate and subsequent activation of kinases, such as calcium/calmodulin-dependent protein kinase II, calcineurin and protein kinase C. Following these events, transcription factors such as nuclear factor of activated T cells are activated (35). Alternatively, activation of the Wnt/PCP pathway begins when Wnt proteins engage with frizzled receptors, triggering DVL protein activation and subsequent activation of ras homologous/RAC guanosine triphosphatases and JNK. These signaling events lead to cytoskeletal rearrangement and regulation of gene expression. Both non-canonical pathways regulate key processes, including cell polarity, migration and signal transduction (36).

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.

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.

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.

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).