PUBLICATION
JUNB governs a feed-forward network of TGFβ signaling that aggravates breast cancer invasion
- Authors
- Sundqvist, A., Morikawa, M., Ren, J., Vasilaki, E., Kawasaki, N., Kobayashi, M., Koinuma, D., Aburatani, H., Miyazono, K., Heldin, C.H., van Dam, H., Ten Dijke, P.
- ID
- ZDB-PUB-190704-12
- Date
- 2018
- Source
- Nucleic acids research 46: 1180-1195 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Base Sequence
- Binding Sites
- Breast Neoplasms/genetics*
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology
- Cell Line
- Cell Line, Tumor
- Embryo, Nonmammalian
- Epithelial Cells/cytology
- Epithelial Cells/drug effects
- Epithelial Cells/metabolism
- Feedback, Physiological*
- Female
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic*
- Gene Regulatory Networks*
- High-Throughput Nucleotide Sequencing
- Humans
- Neoplasm Invasiveness
- Protein Binding
- Smad2 Protein/genetics
- Smad2 Protein/metabolism
- Smad3 Protein/genetics
- Smad3 Protein/metabolism
- Transcription Factors/genetics*
- Transcription Factors/metabolism
- Transforming Growth Factor beta1/metabolism
- Transforming Growth Factor beta1/pharmacology*
- Wnt Proteins/genetics
- Wnt Proteins/metabolism
- Wnt Signaling Pathway
- Zebrafish
- PubMed
- 29186616 Full text @ Nucleic Acids Res.
Citation
Sundqvist, A., Morikawa, M., Ren, J., Vasilaki, E., Kawasaki, N., Kobayashi, M., Koinuma, D., Aburatani, H., Miyazono, K., Heldin, C.H., van Dam, H., Ten Dijke, P. (2018) JUNB governs a feed-forward network of TGFβ signaling that aggravates breast cancer invasion. Nucleic acids research. 46:1180-1195.
Abstract
It is well established that transforming growth factor-β (TGFβ) switches its function from being a tumor suppressor to a tumor promoter during the course of tumorigenesis, which involves both cell-intrinsic and environment-mediated mechanisms. We are interested in breast cancer cells, in which SMAD mutations are rare and interactions between SMAD and other transcription factors define pro-oncogenic events. Here, we have performed chromatin immunoprecipitation (ChIP)-sequencing analyses which indicate that the genome-wide landscape of SMAD2/3 binding is altered after prolonged TGFβ stimulation. De novo motif analyses of the SMAD2/3 binding regions predict enrichment of binding motifs for activator protein (AP)1 in addition to SMAD motifs. TGFβ-induced expression of the AP1 component JUNB was required for expression of many late invasion-mediating genes, creating a feed-forward regulatory network. Moreover, we found that several components in the WNT pathway were enriched among the late TGFβ-target genes, including the invasion-inducing WNT7 proteins. Consistently, overexpression of WNT7A or WNT7B enhanced and potentiated TGFβ-induced breast cancer cell invasion, while inhibition of the WNT pathway reduced this process. Our study thereby helps to explain how accumulation of pro-oncogenic stimuli switches and stabilizes TGFβ-induced cellular phenotypes of epithelial cells.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping