title: The EMT-activator ZEB1 induces bone metastasis associated genes including BMP-inhibitors.
abstract: Tumor cell invasion, dissemination and metastasis is triggered by an aberrant activation of epithelial-to-mesenchymal transition (EMT), often mediated by the transcription factor ZEB1. Disseminating tumor cells must acquire specific features that allow them to colonize at different organ sites. Here we identify a set of genes that is highly expressed in breast cancer bone metastasis and activated by ZEB1. This gene set includes various secreted factors, e.g. the BMP-inhibitor FST, that are described to reorganize the bone microenvironment. By inactivating BMP-signaling, BMP-inhibitors are well-known to induce osteolysis in development and disease. We here demonstrate that the expression of ZEB1 and BMP-inhibitors is correlated with bone metastasis, but not with brain or lung metastasis of breast cancer patients. In addition, we show that this correlated expression pattern is causally linked, as ZEB1 induces the expression of the BMP-inhibitors NOG, FST and CHRDL1 both by directly increasing their gene transcription, as well as by indirectly suppressing their reduction via miR-200 family members. Consequently, ZEB1 stimulates BMP-inhibitor mediated osteoclast differentiation. These findings suggest that ZEB1 is not only driving EMT, but also contributes to the formation of osteolytic bone metastases in breast cancer.
authors.affiliation: Department of Visceral Surgery, University Medical Center Freiburg, Freiburg, Germany.|Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Mock
authors.affiliation: Department of Visceral Surgery, University Medical Center Freiburg, Freiburg, Germany.|Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Bogdan-Tiberius
authors.initials: BT
authors.lastname: Preca
authors.affiliation: Institute of Molecular Medicine and Cell Research, University Medical Center Freiburg, Germany and Center for Biological Signalling Studies BIOSS, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Brummer
authors.affiliation: Department of Experimental Medicine I, Nikolaus-Fiebiger-Center for Molecular Medicine, University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Brabletz
authors.affiliation: Department of Experimental Medicine I, Nikolaus-Fiebiger-Center for Molecular Medicine, University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Stemmler
authors.affiliation: Department of Experimental Medicine I, Nikolaus-Fiebiger-Center for Molecular Medicine, University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brabletz
mesh_terms: D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors*; D001859:Bone Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D019485:Bone Morphogenetic Proteins; D018398:Homeodomain Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1
keywords: BMP-inhibitor; ZEB1; bone metastasis; breast cancer; epithelial-mesenchymal transition (EMT)