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J. Clin. Med. 2019, 8(2), 148; https://doi.org/10.3390/jcm8020148

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

1
International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei City 11031, Taiwan
2
Doctorate Program of Medical and Health Science, Faculty of Medicine Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
3
Department of Hematology & Oncology, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
4
Department of Medical Research & Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
5
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City 11031, Taiwan
6
Division of Medical Oncology and Hematology, Tri-Service General Hospital, National Defense Medical Centre, Taipei 11409, Taiwan
7
Department of Surgery, Faculty of Medicine Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
8
Department of Histology and Cellular Biology, Faculty of Medicine Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
*
Authors to whom correspondence should be addressed.
Received: 6 December 2018 / Revised: 19 January 2019 / Accepted: 22 January 2019 / Published: 27 January 2019
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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. View Full-Text
Keywords: Cadherin 11; WNT signaling; β-catenin; cancer stem cells; TNBC Cadherin 11; WNT signaling; β-catenin; cancer stem cells; TNBC
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Satriyo, P.B.; Bamodu, O.A.; Chen, J.-H.; Aryandono, T.; Haryana, S.M.; Yeh, C.-T.; Chao, T.-Y. 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. J. Clin. Med. 2019, 8, 148.

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