Twist1 accelerates tumour vasculogenic mimicry by inhibiting Claudin15 expression in triple-negative breast cancer.

Danfang Zhang,Xiulan Zhao,Zhiqiang Qiu,Dongwang Zhu,Fang Liu,Jindan An,Baocun Sun,Yanhui Zhang,Na Che,Xian Lin,Xueyi Dong,Jing Li,Jiameng Liu,Xu Zheng,Xudong Wang,Qing Gu ,Yong Li ,Hongxia Sun ,Xiao‐Fan Zhao ,Run-Fen Cheng ,Quan Hong

doi:10.1111/jcmm.15167

Danfang Zhang, Xiulan Zhao + Show 19 more

Open Access

PDF Available

https://doi.org/10.1111/jcmm.15167

Copy DOI

Export

Save

Cite

Abstract
Highlights/Summary
Full-Text PDF
Similar Papers

Abstract

Listen

The up‐regulation of EMT regulator Twist1 has been implicated in vasculogenic mimicry (VM) formation in human triple‐negative breast cancer (TNBC). Twist1 targets the Claudin15 promoter in hepatocellular carcinoma cells. Claudin family members are related with TNBC. However, the relationship between Claudin15 and VM formation is not clear. In this study, we first found that Claudin15 expression was frequently down‐regulated in human TNBC, and Claudin15 down‐regulation was significantly associated with VM and Twist1 nuclear expression. Claudin15 down‐regulation correlated with shorter survival compared with high levels. Claudin15 silence significantly enhanced cell motility, invasiveness and VM formation in the non‐TNBC MCF‐7 cells. Conversely, an up‐regulation of Claudin15 remarkably reduced TNBC MDA‐MB‐231 cell migration, invasion and VM formation. We also showed that down‐regulation of Claudin15 was Twist1‐dependent, and Twist1 repressed Claudin15 promoter activity. Furthermore, GeneChip analyses of mammary glands of Claudin15‐deficient mice indicated that Claudin18 and Jun might be downstream factors of Twist1‐Claudin15. Our results suggest that Twist1 induced VM through Claudin15 suppression in TNBC, and Twist1 inhibition of Claudin15 might involve Claudin18 and Jun expression.

Highlights

Breast cancer is the most frequent malignancy among women worldwide.[1]
In this study we examined the hypothesis that Twist[1] binds to Claudin[15] promoter to inhibit its expression to promote vasculogenic mimicry (VM) formation
Twist[1] overexpression resulted in an approximate fivefold transactivation inhibition of Claudin[15] promoter activity (Figure 3E). These results suggest that the Claudin[15] promoter is a target of Twist[1] binding in breast cancer cells

Summary

| INTRODUCTION

Breast cancer is the most frequent malignancy among women worldwide.[1]. Triple-negative breast cancer (TNBC) cells do not express oestrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor receptor 2 (HER2)[2] and account for 15-26% of breast cancer cases.[3,4] TNBC cases show significant differences in incidence, survival and response to therapy compared. Claudin-low breast cancer is the most recently identified subtype.[10]. This distinct subtype is characterized by the low gene expression of tight junction proteins Claudins 3, 4 and 7, and E-cadherin and the high gene expression of epithelial-to-mesenchymal transition (EMT)-associated molecules.[10]. The full Claudin expression profile and functions in different tumours are still not well characterized.[16]. EMT-inducing transcription factors, including Slug, Twist[1], Zinc finger E-box binding homeobox 2 (ZEB2) and bone morphogenetic protein 2 (BMP2), are associated with VM existence in different malignant tumours.[26,31-33]. We found that Twist[1] bound to the Claudin[15] promoter in hepatocellular carcinoma cells.[34] Based on these results, in this study we examined the hypothesis that Twist[1] binds to Claudin[15] promoter to inhibit its expression to promote VM formation

| MATERIAL AND METHODS

Findings

| DISCUSSION