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

被引：49

作者：

Satriyo, Pamungkas Bagus ^{[1
,2
]}

Bamodu, Oluwaseun Adebayo ^{[3
,4
]}

Chen, Jia-Hong ^{[5
,6
]}

Aryandono, Teguh ^{[7
]}

Haryana, Sofia Mubarika ^{[8
]}

Yeh, Chi-Tai ^{[1
,3
,4
,5
]}

Chao, Tsu-Yi ^{[1
,3
,4
,5
,6
]}

机构：

[1] Taipei Med Univ, Coll Med, Int PhD Program Med, Taipei 11031, Taiwan

[2] Univ Gadjah Mada, Fac Med Publ Hlth & Nursing, Doctorate Program Med & Hlth Sci, Yogyakarta 55281, Indonesia

[3] Taipei Med Univ, Dept Hematol & Oncol, Shuang Ho Hosp, New Taipei 23561, Taiwan

[4] Taipei Med Univ, Dept Med Res & Educ, Shuang Ho Hosp, New Taipei 23561, Taiwan

[5] Taipei Med Univ, Coll Med, Grad Inst Clin Med, Taipei 11031, Taiwan

[6] Natl Def Med Ctr, Triserv Gen Hosp, Div Med Oncol & Hematol, Taipei 11409, Taiwan

[7] Univ Gadjah Mada, Fac Med Publ Hlth & Nursing, Dept Surg, Yogyakarta 55281, Indonesia

[8] Univ Gadjah Mada, Fac Med Publ Hlth & Nursing, Dept Histol & Cellular Biol, Yogyakarta 55281, Indonesia

来源：

JOURNAL OF CLINICAL MEDICINE | 2019年 / 8卷 / 02期

关键词：

Cadherin; 11; WNT signaling; beta-catenin; cancer stem cells; TNBC; EXPRESSION;

D O I：

10.3390/jcm8020148

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 beta-catenin, wingless type MMTV integration site (WNT)2, and transcription factor (TCF)12 expression. IHC results showed CDH11 and beta-catenin expression significantly correlated in TNBC patients (p < 0.05). We also showed that siRNA-mediated loss-of-CDH11 (siCDH11) function decreases beta-catenin, Met, c-Myc, and matrix metalloproteinase (MMP)7 expression level in MDA-MB-231 and Hs578t. Interestingly, immunofluorescence staining showed that siCDH11 reduced beta-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 beta-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.

引用

页数：17