PUBLICATION
Reactivation of BMP signaling by suboptimal concentrations of MEK inhibitor and FK506 reduces organ-specific breast cancer metastasis
- Authors
- Ren, J., Wang, Y., Ware, T., Iaria, J., Ten Dijke, P., Zhu, H.J.
- ID
- ZDB-PUB-200810-32
- Date
- 2020
- Source
- Cancer letters 493: 41-54 (Journal)
- Registered Authors
- Keywords
- BMP, Breast cancer metastasis, FK506, TGFβ, U0126
- MeSH Terms
-
- Animals
- Bone Morphogenetic Proteins/genetics
- Breast Neoplasms/drug therapy*
- Breast Neoplasms/genetics
- Butadienes/administration & dosage
- Butadienes/pharmacology
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Cell Survival/drug effects
- Drug Synergism
- Female
- Flavonoids/administration & dosage
- Flavonoids/pharmacology
- Gene Expression Regulation, Neoplastic/drug effects
- Humans
- MCF-7 Cells
- Mice
- NIH 3T3 Cells
- Neoplasm Metastasis
- Nitriles/administration & dosage
- Nitriles/pharmacology
- Organ Specificity
- Protein Kinase Inhibitors/administration & dosage*
- Protein Kinase Inhibitors/pharmacology
- Signal Transduction/drug effects*
- Tacrolimus/administration & dosage*
- Tacrolimus/pharmacology
- Xenograft Model Antitumor Assays
- Zebrafish
- PubMed
- 32768522 Full text @ Cancer Lett.
Citation
Ren, J., Wang, Y., Ware, T., Iaria, J., Ten Dijke, P., Zhu, H.J. (2020) Reactivation of BMP signaling by suboptimal concentrations of MEK inhibitor and FK506 reduces organ-specific breast cancer metastasis. Cancer letters. 493:41-54.
Abstract
TGFβ-SMAD3 signaling is a major driving force for cancer metastasis, while BMP-SMAD1/5 signaling can counteract this response. Analysis of gene expression profiles reveal that not only is increased TGFβ-SMAD3 targeted gene expression signature correlated with shortened distant metastasis free survival and overall survival of patients, but also with reduced BMP-SMAD1/5 targeted gene signature. At molecular levels, we discovered that TGFβ abolished BMP-induced SMAD1/5 activation in the highly-invasive breast cancer MDA-MB-231 cells, but to a less extent in the non-invasive and normal breast cells. This suggests an inverse correlation between BMP signaling and invasiveness of tumor cells and TGFβ signaling acts in a double whammy fashion in driving cancer invasion and metastasis. Sustained ERK activation by TGFβ was specifically observed in MDA-MB-231 cells, and MEK inhibitor (MEKi) treatment restored BMP-SMAD1/5 signaling while not affecting SMAD2/3 activation. FK506 potently activated BMP, but not TGFβ signaling in breast cancer cells. MEKi or FK506 alone inhibited MDA-MB-231 extravasation in zebrafish cancer model. Importantly, when administrated at suboptimal concentrations MEKi and FK506 strongly synergized in promoting BMP-SMAD1/5 signaling and inhibiting cancer cell extravasation. Furthermore, this combination of suboptimal concentrations treatment in a mouse tumor model resulted in real-time reduction of BMP-SMAD1/5 signalling in live tumors, and consequently potently inhibited tumor self-seeding, liver and bone metastasis, but not lung and brain metastasis. Mechanistically, it's the first time to identify BMP-SMAD1/5 signaling as an underlining molecular driver for organ-specific metastasis. Combining of MEKi and FK506, or their analogues, may be explored for clinical development of breast cancer.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping