Cadherin 11 Inhibition Downregulates β-catenin, Deactivates the Canonical WNT Signalling Pathway and Suppresses the Cancer Stem Cell-Like Phenotype of Triple Negative Breast Cancer

Abstract

Background: Cancer stem cells (CSCs) promote tumor progression and distant metastasis in breast cancer. Cadherin 11 (CDH11) is overexpressed in invasive breast cancer cells and implicated in distant bone metastases in several cancers. The WNT signalling pathway regulates CSC activity. Growing evidence suggest that cadherins play critical roles in WNT signalling pathway. However, CDH11 role in canonical WNT signalling and CSCs in breast cancer is poorly understood. Methods: We investigated the functional association between CDH11 and WNT signalling pathway in triple negative breast cancer (TNBC), by analyzing their expression profile in the TCGA Breast Cancer (BRCA) cohort and immunohistochemical (IHC) staining of TNBC samples. Results: We observed a significant correlation between high CDH11 expression and poor prognosis in the basal and TNBC subtypes. Also, CDH11 expression positively correlated with β-catenin, wingless type MMTV integration site (WNT)2, and transcription factor (TCF)12 expression. IHC results showed CDH11 and β-catenin expression significantly correlated in TNBC patients (p < 0.05). We also showed that siRNA-mediated loss-of-CDH11 (siCDH11) function decreases β-catenin, Met, c-Myc, and matrix metalloproteinase (MMP)7 expression level in MDA-MB-231 and Hs578t. Interestingly, immunofluorescence staining showed that siCDH11 reduced β-catenin nuclear localization and attenuated TNBC cell migration, invasion and tumorsphere-formation. Of translational relevance, siCDH11 exhibited significant anticancer efficacy in murine tumor xenograft models, as demonstrated by reduced tumor-size, inhibited tumor growth and longer survival time. Conclusions: Our findings indicate that by modulating β-catenin, CDH11 regulates the canonical WNT signalling pathway. CDH11 inhibition suppresses the CSC-like phenotypes and tumor growth of TNBC cells and represents a novel therapeutic approach in TNBC treatment.

The Missing Lnc: The Potential of Targeting Triple-Negative Breast Cancer and Cancer Stem Cells by Inhibiting Long Non-Coding RNAs

“…In fact, the gene expression signatures of TNBCs exhibited striking similarities to those of mammary stem cells [22]. The developmental Wnt/β-catenin, Notch, and Hedgehog (Hh) pathways are also more active in both CSCs and TNBC [23][24][25].…”

Cadherin-11 is required for neural crest determination and survival

“…For explant assays, embryos were electroporated with 0.75 mM CDH11MO plus Sirius carrier DNA on the right side of the embryo at HH4. Embryos were cultured until HH8 as described previously (Sauka-Spengler and Barembaum, 2008). At HH8, the neural tubes were dissected out of the embryo in Ringer's solution and subsequently placed in 8-well chamber slides (Millicell EZ SLIDE 8-well glass, sterile, # PEZGS0816) that were coated with 1% fibronectin.…”

“…Here, we focus on the identifying the role of Cadherin-11 (CDH11) during early avian embryogenesis. CDH11 has been identified as a Wnt signaling target and effector in developmental and disease systems (Chalpe et al, 2010;Hadeball et al, 1998;Satriyo et al, 2019). Originally defined as a mesenchymal marker with no expression in the undifferentiated neural tube in mouse embryos (Hoffmann and Balling, 1995), the transcript was subsequently reported in developing mouse neuroepithelia (Kimura et al, 1995;, as well as migratory NC cells in chick and frog embryos (Chalpe et al, 2010;Vallin et al, 1998).…”

“…Both reduced and increased levels of CDH11 are linked to patient survival and reduced metastasis in numerous cancers, however, its role is contrasting in different cancer cell types (Carmona et al, 2012;Lee et al, 2013). Specifically, high levels of CDH11 expression have been linked to poor prognosis in gastric cancer and triplenegative breast cancer (Chen et al, 2018;Satriyo et al, 2019), yet it maintains a pro-apoptotic tumor suppressor role in others (Li et al, 2012;Marchong et al, 2010). Although studies have linked CDH11 to NC migration in early development, there is less known about how the protein regulates NC induction, specification, maintenance, or survival.…”

Post-EMT: Cadherin-11 mediates cancer hijacking fibroblasts

“…Optimal cadherin based adherens junction formation is achieved by one type of cadherin binds to the "same" type of cadherin on the other cell in trans 30,31 . Previous studies on cadherin-11 mediated cancer growth and progression in xenograft mouse models were done by implanting human breast cancer cells (with "human" cadherin-11) into the mouse stroma 44,45 . It needs to be pointed out that mouse stromal fibroblasts express "mouse" cadherin-11 but not "human" cadherin-11.…”