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

• Published in: Scientific reports Vol. 9; no. 1; pp. 11724 - 14
• Main Authors: Choi, Sanghyuk, Yu, Jinyeong, Park, Aran, Dubon, Maria Jose, Do, Jungbeom, Kim, Youngjae, Nam, Donghyun, Noh, Jinok, Park, Ki-Sook
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.08.2019; Nature Publishing Group
• Subjects: 631/67/1347; 631/67/71; 96/100; Animals; Bone morphogenetic protein 4; Bone Morphogenetic Protein 4 - genetics; Bone Morphogenetic Protein 4 - metabolism; Breast cancer; Breast carcinoma; Cadherins; CD44 antigen; Cell activation; Cell Line, Tumor; Cell Movement - genetics; Disease Models, Animal; Efficiency; Epithelial cells; Epithelial-Mesenchymal Transition - genetics; Female; Fibronectin; Humanities and Social Sciences; Humans; Laminin; Mammary gland; Mesenchyme; Mice; multidisciplinary; N-Cadherin; Neoplasms - etiology; Neoplasms - metabolism; Neoplasms - pathology; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Receptors, Notch - metabolism; Science; Science (multidisciplinary); Signal Transduction; siRNA; Smad4 protein; Smad4 Protein - genetics; Smad4 Protein - metabolism; Stem cells; Tumorigenesis; Xenograft Model Antitumor Assays
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-48190-5

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.