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

Authors
  • Ren, Jiang1
  • Wang, Yanhong2
  • Ware, Thomas3
  • Iaria, Josephine4
  • Ten Dijke, Peter5
  • Zhu, Hong-Jian6
  • 1 Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2300 RC, Leiden, the Netherlands. Electronic address: [email protected] , (Netherlands)
  • 2 Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville, 3050, Victoria, Australia. Electronic address: [email protected] , (Australia)
  • 3 Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville, 3050, Victoria, Australia. Electronic address: [email protected] , (Australia)
  • 4 Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville, 3050, Victoria, Australia. Electronic address: [email protected] , (Australia)
  • 5 Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2300 RC, Leiden, the Netherlands. Electronic address: [email protected] , (Netherlands)
  • 6 Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville, 3050, Victoria, Australia. Electronic address: [email protected] , (Australia)
Type
Published Article
Journal
Cancer letters
Publication Date
Aug 06, 2020
Volume
493
Pages
41–54
Identifiers
DOI: 10.1016/j.canlet.2020.07.042
PMID: 32768522
Source
Medline
Keywords
Language
English
License
Unknown

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. Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

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