PUBLICATION
Smad6 determines BMP-regulated invasive behaviour of breast cancer cells in a zebrafish xenograft model
- Authors
- de Boeck, M., Cui, C., Mulder, A.A., Jost, C.R., Ikeno, S., Ten Dijke, P.
- ID
- ZDB-PUB-160427-6
- Date
- 2016
- Source
- Scientific Reports 6: 24968 (Journal)
- Registered Authors
- Keywords
- Cell invasion, Transforming growth factor beta
- MeSH Terms
-
- Animals
- Bone Morphogenetic Proteins/metabolism*
- Breast Neoplasms/genetics
- Breast Neoplasms/metabolism*
- Cell Line, Tumor
- Cell Movement
- Coculture Techniques
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Neoplasm Invasiveness
- Neoplasm Transplantation
- Receptors, Estrogen/metabolism
- Signal Transduction
- Smad6 Protein/genetics*
- Smad6 Protein/metabolism*
- Survival Analysis
- Up-Regulation
- Zebrafish
- PubMed
- 27113436 Full text @ Sci. Rep.
Citation
de Boeck, M., Cui, C., Mulder, A.A., Jost, C.R., Ikeno, S., Ten Dijke, P. (2016) Smad6 determines BMP-regulated invasive behaviour of breast cancer cells in a zebrafish xenograft model. Scientific Reports. 6:24968.
Abstract
The transforming growth factor-β (TGF-β) family is known to play critical roles in cancer progression. While the dual role of TGF-β is well described, the function of bone morphogenetic proteins (BMPs) is unclear. In this study, we established the involvement of Smad6, a BMP-specific inhibitory Smad, in breast cancer cell invasion. We show that stable overexpression of Smad6 in breast cancer MCF10A M2 cells inhibits BMP signalling, thereby mitigating BMP6-induced suppression of mesenchymal marker expression. Using a zebrafish xenograft model, we demonstrate that overexpression of Smad6 potentiates invasion of MCF10A M2 cells and enhances the aggressiveness of breast cancer MDA-MB-231 cells in vivo, whereas a reversed phenotype is observed after Smad6 knockdown. Interestingly, BMP6 pre-treatment of MDA-MB-231 cells induced cluster formation at the invasive site in the zebrafish. BMP6 also stimulated cluster formation of MDA-MB-231 cells co-cultured on Human Microvascular Endothelial Cells (HMEC)-1 in vitro. Electron microscopy illustrated an induction of cell-cell contact by BMP6. The clinical relevance of our findings is highlighted by a correlation of high Smad6 expression with poor distant metastasis free survival in ER-negative cancer patients. Collectively, our data strongly indicates the involvement of Smad6 and BMP signalling in breast cancer cell invasion in vivo.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping