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

Sci Rep. 2019 Aug 13;9(1):11724. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Protein 4 / genetics*
  • Bone Morphogenetic Protein 4 / metabolism
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Disease Models, Animal
  • Epithelial-Mesenchymal Transition / genetics*
  • Female
  • Humans
  • Mice
  • Neoplasms / etiology*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Receptors, Notch / metabolism*
  • Signal Transduction*
  • Smad4 Protein / genetics
  • Smad4 Protein / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • BMP4 protein, human
  • Bone Morphogenetic Protein 4
  • Receptors, Notch
  • SMAD4 protein, human
  • Smad4 Protein