Role of the Wnt signaling pathway in the complex microenvironment of breast cancer and prospects for therapeutic potential (Review)

Abstract

The focus on breast cancer treatment has shifted from the cytotoxic effects of single drugs on tumor cells to multidimensional multi‑pathway synergistic intervention strategies targeting the tumor microenvironment (TME). The activation of the Wnt signaling pathway in the TME of breast cancer cells serves a key regulatory role in tissue homeostasis and is a key driver of the carcinogenic process. Modulating the crosstalk between the Wnt pathway and TME of breast cancer is key for understanding the biological behavior of breast cancer and advancing the development of novel antitumor drugs. The present review aimed to summarize the complex mechanisms of the Wnt signaling pathway in the breast cancer TME, interactions between the Wnt signaling pathway and components of the breast cancer TME and breast cancer‑associated genes, as well as the interactions between the Wnt signaling pathway and other signaling cascades at the molecular level. Furthermore, the present review aimed to highlight the unique advantages of the Wnt signaling pathway in the macro‑regulation of the TME and the current therapeutic strategies targeting the Wnt signaling pathway, their potential clinical value and future research directions in breast cancer treatment.

Keywords: Wnt signaling pathway; breast cancer; pathway crosstalk; targeted therapy; tumor microenvironment.

Figure 1

Schematic diagram of canonical and non-canonical signaling pathways. The primary mechanism of the canonical Wnt/β-catenin signaling pathway is to inhibit the degradation of β-catenin and promote the transcription of TCF/LEF genes. The non-canonical PCP pathway activates RHOA and RAC1 via phosphorylation and stimulates JNK; the non-canonical Ca²⁺ pathway is activated by PLC, leading to increased Ca²⁺ concentration and activation of the corresponding pathways. TCF/LEF, T cell factor/lymphoid enhancer-binding factor; PCP, planar cell polarity; PLC, phospholipase C; RHOA, ras homolog family member A; CK, casein kinase; GSK, glycogen synthase kinase; DVL, dishevelled; APC, adenomatous polyposis coli; DAAM, dishevelled associated activator of morphogenesis; LRP, lipoprotein receptor-related protein; ROCK, rho-associated coiled-coil containing protein kinase; CAMKII, calcium/calmodulin-dependent protein kinase II; PKC, protein kinase C; NFAT, nuclear factor of activated T cells; CDC42, cell division cycle 42; TAK, TGF-β-activated kinase; NLK, nemo-like kinase.

Figure 2

Wnt/β-catenin pathway activation and inhibition. Activation of the Wnt signaling pathway leads to the formation of the Wnt-FZD-LRP complex, which suppresses GSK-3β activity, preventing normal phosphorylation of β-catenin and subsequent binding with TCF/LEF transcription factors in the nucleus to activate downstream target genes. Inhibition of the Wnt signaling pathway results in normal degradation of β-catenin, precluding its entry into the nucleus for transcription. TCF/LEF, T cell factor/lymphoid enhancer-binding factor; LRP, lipoprotein receptor-related protein; GSK-3β, glycogen synthase kinase-3β; FZD, frizzled; APC, adenomatous polyposis coli; CK1, casein kinase 1; DVL, dishevelled.

Figure 3

Wnt signaling within the breast cancer TME. Macrophages, T cells, regulatory T cells, fibroblasts, mesenchymal cells, VEGF and exosomes interact with the Wnt signaling pathway in the breast cancer TME. The hypoxic microenvironment, mechanical stress and tumor acidity also influence the Wnt signaling pathway. TME, tumor microenvironment; VEGF, vascular endothelial growth factor; TAM, tumor-associated macrophage; CCL, C-C motif chemokine ligand; DKK, dickkopf; DVL, dishevelled; SMA, smooth muscle actin; CAF, cancer-associated fibroblast; NRP, neuropilin; BMDC, bone marrow-derived dendritic cell; NUMB, protein numb homolog; ABCD, ATP-binding cassette sub-family D; miR, microRNA; RYK, receptor-like tyrosine kinase; RBM5-AS1, RNA binding motif protein 5 antisense RNA 1; HIF, hypoxia-inducible factor; GSK, glycogen synthase kinase; MCI, mitochondrial complex I; TCF, T cell factor; CiDA, compression-induced dedifferentiated adipocyte; Gli2, GLI family zinc finger 2; PTHrP, parathyroid hormone-related protein.

Figure 4

Interaction between the Wnt signaling pathway and other pathways in the breast cancer TME. Wnt signaling interacts with TGF-β, PI3K/Akt, FGF and hedgehog signaling pathways within the TME. TME, tumor microenvironment; FGF, fibroblast growth factor; TGF, tumor growth factor; PI3K, phosphatidylinositol-3 kinase; Hh, hedgehog; PTCH, patched; SMO, smoothened; LRP, lipoprotein receptor-related protein; TβR, transforming growth factor-beta receptor; SARA, Smad anchor for receptor activation; Kif, kinesin family member; GLIA, GLI family zinc finger; SUFU, suppressor of fused; sFRP, secreted frizzled-related protein; Gli, GLI family zinc finger; Shh, sonic hedgehog; TCF/LEF, T-cell factor/Lymphoid enhancer factor; CAF, cancer-associated fibroblast; CSC, cancer stem cell; EC, endothelial cell; EMT, epithelial-mesenchymal transition; DVL, dishevelled; APC, adenomatous polyposis coli; CK, casein kinase; GSK, glycogen synthase kinase; NFAT, nuclear factor of activated T cell; IP3, inositol trisphosphate; PIP, phosphatidylinositol phosphate; PLC, phospholipase C; Lg, ligand; DAG, diacylglycerol; FRS, fibroblast growth factor receptor substrate; SHP, Src homology 2 domain-containing phosphatase; GRB, growth factor receptor-bound protein; GAB, GRB2-associated binder; SOS, son of sevenless; P85α, phosphoinositide-3-kinase regulatory subunit α; MR-3, 3,5,4'-trimethoxystilbene; RTK, receptor tyrosine kinase; GF, growth factor; PDK, phosphoinositide-dependent kinase; EMT, epithelial-mesenchymal transition; mTOR, mammalian target of rapamycin.

Figure 5

Drugs targeting the Wnt signaling pathway in breast cancer. Therapeutic strategies for inhibiting the Wnt pathway include PORCN and LRP5/6 inhibitors, frizzled receptor antagonists, tankyrase inhibitors and natural compounds. LRP, lipoprotein receptor-related protein; PORCN, porcupine; TME, tumor microenvironment.