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.
Highlights
Triple negative breast cancer (TNBC) constitutes 10−20% of all breast cancer cases and exhibits more aggressive traits and worse patient prognosis than hormone receptor- and HER2- positive breast cancer [1]
Our data is consistent with the aggressive phenotype of triple negative breast cancer (TNBC) cells and their poor prognosis despite initial good response to therapy and corroborate significant overlap between the TNBC and BL breast cancer molecular subtypes [22,23]
Since the Cancer stem cells (CSCs)-like phenotype is often associated with enhanced oncogenicity and metastatic traits [24], we further examined whether and how alteration in Cadherin 11 (CDH11) expression affects the characteristic aggressiveness of TNBC cells, using wild type (WT) and siRNA-mediated loss-of-CDH11 (siCDH11) MDA-MB-231 and Hs578t cells
Summary
Triple negative breast cancer (TNBC) constitutes 10−20% of all breast cancer cases and exhibits more aggressive traits and worse patient prognosis than hormone receptor- and HER2- positive breast cancer [1]. The discovery and development of novel efficacious targeted therapy to treat TNBC and prevent metastatic breast disease are important issues. 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. IHC results showed CDH11 and β-catenin expression significantly correlated in TNBC patients (p < 0.05). Immunofluorescence staining showed that siCDH11 reduced β-catenin nuclear localization and attenuated TNBC cell migration, invasion and tumorsphere-formation. CDH11 inhibition suppresses the CSC-like phenotypes and tumor growth of TNBC cells and represents a novel therapeutic approach in TNBC treatment
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