Reactivation of BMP signaling by suboptimal concentrations of MEK inhibitor and FK506 reduces organ-specific breast cancer metastasis.

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 revealed that an increased TGFβ-SMAD3 and a reduced BMP-SMAD1/5 targeted gene expression signature correlated with shortened distant metastasis free survival and overall survival of patients. 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 cancer 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 a zebrafish xenograft 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 signaling in live tumors, and consequently potently inhibited tumor self-seeding, liver and bone metastasis, but not lung and brain metastasis. Mechanistically, it is the first time to identify BMP-SMAD1/5 signaling as an underlying molecular driver for organ-specific metastasis. Combining of MEKi and FK506, or their analogues, may be explored for clinical development of breast cancer.

• Authors: Jiang Ren, Yanhong Wang, Thomas Ware, Josephine Iaria, Peter Ten Dijke, Hong-Jian Zhu
• Journal: Cancer letters (Cancer Lett) Vol. 493 Pg. 41-54 (11 28 2020) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 32768522 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Bone Morphogenetic Proteins
• Butadienes
• Flavonoids
• Nitriles
• Protein Kinase Inhibitors
• U 0126
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
• Tacrolimus

Topics

• Animals
• Bone Morphogenetic Proteins (genetics)
• Breast Neoplasms (drug therapy, genetics)
• Butadienes (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Synergism
• Female
• Flavonoids (administration & dosage, pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• MCF-7 Cells
• Mice
• NIH 3T3 Cells
• Neoplasm Metastasis
• Nitriles (administration & dosage, pharmacology)
• Organ Specificity
• Protein Kinase Inhibitors (administration & dosage, pharmacology)
• Signal Transduction (drug effects)
• Tacrolimus (administration & dosage, pharmacology)
• Xenograft Model Antitumor Assays
• Zebrafish