title: Tamoxifen Inhibits TGF-β-Mediated Activation of Myofibroblasts by Blocking Non-Smad Signaling Through ERK1/2.
abstract: Transforming growth factor-β (TGF-β) is a multifunctional cytokine which stimulates the differentiation of fibroblasts into myofibroblasts. Myofibroblasts are critical for normal wound healing, but also accumulate pathologically in a number of chronic inflammatory conditions where they are key contributors to aberrant tissue remodeling and fibrosis, and in cancer stroma. In the current study, we identified a role for tamoxifen as a potent inhibitor of the TGF-β-mediated activation of primary human skin and breast fibroblasts. Our data indicate that tamoxifen does not interfere with canonical Smad signaling downstream of TGF-β but rather blocks non-Smad signaling through ERK1/2 MAP-kinase and the AP-1 transcription factor FRA2. We further demonstrate by siRNA-mediated knockdown that FRA2 is critical for the induced expression of myogenic proteins in response to TGF-β. Functionally, TGF-β-stimulated fibroblast-mediated contraction of collagen gels was impaired in the presence of tamoxifen. Altogether, these data demonstrate that tamoxifen prevents myofibroblast differentiation and, therefore, may provide therapeutic benefits to patients suffering from chronic inflammatory conditions or cancer.
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Biomedical Center, Uppsala University, Uppsala, Sweden.
authors.forename: Jon M
authors.initials: JM
authors.lastname: Carthy
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Biomedical Center, Uppsala University, Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Sundqvist
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Biomedical Center, Uppsala University, Uppsala, Sweden.
authors.forename: Angelos
authors.initials: A
authors.lastname: Heldin
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Biomedical Center, Uppsala University, Uppsala, Sweden.|Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: van Dam
authors.affiliation: Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, Greece.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Kletsas
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Biomedical Center, Uppsala University, Uppsala, Sweden.
authors.forename: Carl-Henrik
authors.initials: CH
authors.lastname: Heldin
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Biomedical Center, Uppsala University, Uppsala, Sweden.|Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Biomedical Center, Uppsala University, Uppsala, Sweden.
authors.forename: Aristidis
authors.initials: A
authors.lastname: Moustakas
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D001940:Breast / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D048430:Cell Shape / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D051921:Fos-Related Antigen-2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D058628:Myofibroblasts / Q000187:drug effects* / Q000201:enzymology; D010641:Phenotype; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects*; D012867:Skin / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D013629:Tamoxifen / Q000494:pharmacology*; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; C497872:FOSL2 protein, human; D051921:Fos-Related Antigen-2; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D013629:Tamoxifen; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3