Triple-negative breast cancer: understanding Wnt signaling in drug resistance

Abstract

Triple-negative breast cancer (TNBC) is not as prevalent as hormone receptor or HER2-positive breast cancers and all receptor tests come back negative. More importantly, the heterogeneity and complexity of the TNBC on the molecular and clinical levels have limited the successful development of novel therapeutic strategies and led to intrinsic or developed resistance to chemotherapies and new therapeutic agents. Studies have demonstrated deregulation of Wnt/β-catenin signaling in tumorigenesis which plays decisive roles at the low survival rate of patients and facilitates resistance to currently existing therapies. This review summarizes mechanisms of Wnt/β-catenin signaling for resistance development in TNBC, the complex interaction between Wnt/β-catenin signaling, and the transactivated receptor tyrosine kinase (RTK) signaling pathways, lymphocytic infiltration, epithelial-mesenchymal transition (EMT), and induction of metastasis. Such associations and how these pathways interact in the development and progression of cancer have led to the careful analysis and development of new and effective combination therapies without generating significant toxicity and resistance.

Keywords: Combination therapy; Drug resistance; Triple negative breast cancers (TNBCs); Tumorigenesis; Wnt/β-catenin.

Fig. 1

An overview of the Wnt signaling pathway. a In the absence of Wnt ligands (Wnt-Off state), β-catenin is released from the cytomembrane, sequestered in a destructive protein complex, that is composed of adenomatous polyposis coli (APC), the scaffolding protein axin, casein kinase 1 (CK1), and glycogen synthase kinase 3β (GSK-3β). The Dkks, WIF, and SFRPs act as antagonists. The phosphorylations by CK1 and GSK-3β recruit β-propeller domain of the E3 ubiquitin ligase (β TrCP) and subsequently cause the β catenin proteasomal degradation and transcriptional repression of Wnt target genes. b Canonical Wnt/β-catenin signaling is activated by binding of Wnt ligands (Wnt-On state) to a receptor complex composed of FZD and LRP 5/6. The recruitment of phosphorylated DVL to FZD inhibits the APC/CK1/GSK-3β destruction complex and blockade of β-catenin by GSK-3β. Accumulated β-catenin in the cytoplasm translocate into the nucleus, where it regulates target gene expression with the Tcf/Lef family of transcription factors. c In Wnt planar cell polarity (Wnt-PCP) signaling, Wnt binds multiple receptors including FZD and co-receptors ROR and Ryk. This activates Rho-A and RAK1/Cdc42, which activate ROCK and JNK (c-Jun N-terminal kinase), respectively, leading to actin cytoskeleton rearrangement and cell polarity through AP-1. d In ON-state non-canonical Wnt/Ca2+ signaling pathway, the binding of Wnt promotes FZD-mediated activation of G proteins and Ryk and initiates the release of Ca2+ from intracellular stores and activation of Ca2+-dependent effector molecules. Several Ca2+-sensitive targets, i.e., PKC, CamKII, and calcineurin, have been identified as downstream of the Wnt/Ca2+ pathway

Fig. 2

Cross-talk of the Wnt/β-catenin pathway with the RTK family receptors and its role in the induction of EMT. The Wnt/β-catenin and EGFR signaling pathways, on the binding of specific ligands, can activate each other. The binding of Wnt ligands with FZD receptors transactivates EGFR signaling by MMP-mediated release of EGF ligands. In turn, EGFR signaling transactivates the Wnt/β-catenin pathway through the PI3K/Akt and Ras/Raf/MEK/Erk signaling cascades. Akt can induce β-catenin by triggering its nuclear translocation or blocking GSK-3β activities. PTEN, which acts as a tumor suppressor and inhibits the activation of Akt, also negatively regulates β-catenin nuclear translocation. In addition, the aberrant activation of the EGFR pathway leads to an increase in free β-catenin accumulation in the cytoplasm through inducing dissociation from α-catenin. Several cell signaling pathways induce the expression of EMT-inducing transcription factors such as ZEB, SNAIL, and TWIST to push the tumor cells toward proliferation and metastasis. Moreover, the binding of several growth factors and cytokines to their receptors acts to induce the phosphorylation and activation of JAKs and activator of transcription proteins (STATs); STAT3/5 dimers stimulate the transcription of genes encoding EMT transcription factors, anti-apoptotic and survival proteins. In addition, in response to stimuli, such as TNF-α, the IKK complex is activated, resulting in phosphorylation of IKB and its degradation by the proteasome, and allowing the translocation of NF-κB into the nucleus

Fig. 3

Schematic overview of β-catenin–MUC1 dynamics. MUC1 interacts with various receptor tyrosine kinases, such as EGFR, FGFR, PDGFR, and HER2. When the serine-rich domain of MUC1-C is phosphorylated by EGFR or cSRC, the affinity for β-catenin binding is increased. Following cleavage of the cytoplasmic domain, the MUC1/β- catenin complex localizes adjacent to the membrane and binds cytoskeleton members (fascin and vinculin), or competitively binds with E-cadherin to prevent E-cadherin/β-catenin complex formation. The formation of the MUC1/β-catenin complex stabilizes β-catenin in the cytoplasm by preventing its phosphorylation-mediated proteasomal degradation. In addition, MUC1-CD/β-catenin is translocated into the nucleus and interacts with (TCF7L2/TCF4) transcription factors to activate Wnt-triggered genes transcription