**5.2. The Wnt/β-catenin pathway**

The Wnt/β-catenin pathway plays an important role in both normal development and tumorigenesis. The initiation of Wnt/β-catenin pathway occurs via conserved growth factors of the wingless and integration site growth factor (Wnt) family. Nineteen different Wnt genes which share a high level of sequence homology encode Wnts. Binding of Wnts to cell surface receptors lead to the activation of Wnt pathway by triggering signaling cascades that are very crucial in many cellular functions including survival, cell proliferation, specification of cell fate, migration and polarity and self-renewal property of stem cells [46]. Canonical Wnt pathway is also known as β-catenin-dependent Wnt pathway. In the absence of this signaling, β-catenin is maintained at a low level via *ubiquitin*/*proteasome*-*mediated degradation*. This can be regulated through protein destruction complex consisting of adenomatous polyposis coli (APC), axin and glycogen synthase kinase-3β (GSK-3β). Binding of Wnt ligand to a seven-pass transmembrane Frizzled (FZD) receptor in combination with its co-receptor, low-density lipoprotein receptor-related protein 6 (LRP6) or its close relative LRP5leads to the activation of Wnt signaling pathway.. The formation of Wnt/FZD/LRP6 complex with the recruitment of the scaffolding protein Disheveled (Dvl) leads to LRP6 phosphorylation and recruitment of the Axin complex to the receptors. As a result, Axin-mediated β-catenin phosphorylation gets inhibited and β-catenin will be stabilized in the cytoplasm. Accumulated β-catenin translocates to the nucleus to form complexes with T cell factor/lymphoid enhancer factor (TCF/LEF) family of proteins and activates target gene expression of Wnt signaling pathway (**Figure 5**) [47].

are also being tested [48]. Thus, effective treatment of TNBC by targeting Wnt signaling pathway is highly anticipated and would prove immensely beneficial in conquering this

Endocrine and Cell Surface Receptor Signaling in Breast Carcinogenesis

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**Figure 5.** Schematic representation of canonical Wnt signaling pathway. Modified from Kazi et al. [46].

We thank King Abdulaziz City for Science and Technology for their support in this work.

deadly disease.

**Acknowledgements**

**Conflict of interest**

**Abbreviation**

The authors declare no conflict of interest.

APC adenomatous polyposis coli

GSK-3β axin and glycogen synthase kinase-3β

ACS American Cancer Society

AIs aromatase inhibitors

It has been noticed that aberrant activation of canonical Wnt pathway, which supports the formation and the maintenance of cancer stem cells (CSCs), maintains the pluripotency of the stem cells instead of allowing them to differentiate leading to neoplastic proliferation. Dysregulation in any components of this pathway accelerates tumor growth [46].

Triple-negative breast cancers (TNBC) is considered to be the most difficult subtype to treat due to the lack of effective targeted therapy. It has been observed that Wnt/β-catenin signaling is activated in TNBC patients with the upregulation of its components. The overactivation of this signaling with the upregulation of Wnt receptor expression in TNBC and basal-like breast cancer (BLBC) advocates this signaling pathway might be utilized as therapeutic target for TNBC/BLBC. For instance, salinomycin has been identified as an inhibitor of LRP6 expression and Wnt/β-catenin signaling and also as a selective killer of breast cancer stem cells. Another example is mesoderm development (Mesd), which has been identified as a specialized chaperone for LRP5/6 and acts as an LRP6 antagonist. Several other Wnt pathway inhibitors are in clinical trials such as OMP-18R5, OMP-54F28 and OTSA101 targeting FZD7, FZD8 and FZD10, respectively, as summarized in **Table 3**. Drugs targeting β-catenin

**Figure 5.** Schematic representation of canonical Wnt signaling pathway. Modified from Kazi et al. [46].

are also being tested [48]. Thus, effective treatment of TNBC by targeting Wnt signaling pathway is highly anticipated and would prove immensely beneficial in conquering this deadly disease.
