Twist-mediated Epithelial-mesenchymal Transition Promotes Breast Tumor Cell Invasion via Inhibition of Hippo Pathway.

Yifan Wang,Binhua P Zhou,Pengnian Charles Lin,Xuhua Ying,Jingyi Liu

doi:10.1038/srep24606

Abstract

Twist is a key transcription factor for Epithelial-mesenchymal transition (EMT), which is a cellular de-differentiation program that promotes invasion and metastasis, confers tumor cells with cancer stem cell (CSC)-like characteristics, and increases therapeutic resistance. However, the mechanisms that facilitate the functions of Twist remain unclear. Here we report that Twist overexpression increased expression of PAR1, an upstream regulator of the Hippo pathway; PAR1 promotes invasion, migration, and CSC-like properties in breast cancer by activating the transcriptional co-activator TAZ. Our study indicates that Hippo pathway inhibition is required for the increased migratory and invasiveness ability of breast cancer cells in Twist-mediated EMT.

Highlights

Breast cancer is the most common cancer in women worldwide, and approximately 90% of breast cancer deaths are the result of metastasis
We found that the expression of Twist induced Epithelial-mesenchymal transition (EMT) in mammary epithelial cells and luminal breast cancer cells, and that PAR1 and TAZ were activated in these Twist-overexpressing transfectants
Our results indicate that the activation of PAR1 and the inhibition of Hippo pathway are required for the Twist-induced EMT

Summary

Introduction

Breast cancer is the most common cancer in women worldwide, and approximately 90% of breast cancer deaths are the result of metastasis. EMT, a phenomenon traditionally associated with embryonic development, is accepted as a central mechanism that induces invasion and metastasis of tumors[2,3]. Twist and Snail are two transcriptional factors that are crucial to EMT activation, and cooperate to support development of full invasive and metastatic capacity. We found that the expression of Twist induced EMT in mammary epithelial cells and luminal breast cancer cells, and that PAR1 and TAZ were activated in these Twist-overexpressing transfectants. Our results indicate that the activation of PAR1 and the inhibition of Hippo pathway are required for the Twist-induced EMT. Our study reveals a critical mechanism underlying metastasis and has implications for the development of therapeutic strategies for breast cancer

Methods

Results

Conclusion