BMP-4 enhances epithelial mesenchymal transition and cancer stem cell properties of breast cancer cells via Notch signaling

Sanghyuk Choi,Ki-Sook Park,Jinyeong Yu,Jungbeom Do,Donghyun Nam,Maria Jose Dubon,Jinok Noh,Aran Park,Youngjae Kim

doi:10.1038/s41598-019-48190-5

Abstract

Bone morphogenetic protein (BMP) signaling and Notch signaling play important roles in tumorigenesis in various organs and tissues, including the breast. BMP-4 enhanced epithelial mesenchymal transition (EMT) and stem cell properties in both mammary epithelial cell line and breast carcinoma cell line. BMP-4 increased the expression of EMT biomarkers, such as fibronectin, laminin, N-cadherin, and Slug. BMP-4 also activated Notch signaling in these cells and increased the sphere forming efficiency of the non-transformed mammary epithelial cell line MCF-10A. In addition, BMP-4 upregulated the sphere forming efficiency, colony formation efficiency, and the expression of cancer stem cell markers, such as Nanog and CD44, in the breast carcinoma cell line MDA-MB-231. Inhibition of Notch signaling downregulated EMT and stem cell properties induced by BMP-4. Down-regulation of Smad4 using siRNA impaired the BMP-4-induced activation of Notch signaling, as well as the BMP-4-mediated EMT. These results suggest that EMT and stem cell properties are increased in mammary epithelial cells and breast cancer cells through the activation of Notch signaling in a Smad4-dependent manner in response to BMP-4.

Highlights

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β (TGF-β) superfamily
BMP-4 induces epithelial mesenchymal transition (EMT) and activates Notch signaling in the MCF-10A human mammary epithelial cell line
As we have reported previously, BMP-4 activated the canonical BMP signaling pathway and induced the epithelial mesenchymal transition (EMT) in the human mammary epithelial cell line MCF-10A (Fig. 1)

Summary

Introduction

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β (TGF-β) superfamily. The activated BMP type 1 receptors phosphorylate Smad1/5/9 proteins, which form a complex with Smad[4] This Smad complex enters the nucleus in order to regulate the expression of BMP downstream genes[12,13]. Www.nature.com/scientificreports the Notch receptor are released intracellularly These intracellular Notch fragments enter the nucleus where they act to regulate the expression of Notch downstream genes, such as Hey[1] and Hes[120,21]. The expression of Notch[1] and Jagged-1 is significantly increased, and their enhanced expression is associated with poor survival, invasion, EMT, and bone metastasis[24,25,26,27,28]. It is known that Notch signaling activated by TGF-β mediates EMT induced by TGF-β132

Methods

Results

Conclusion