title: A novel ZEB1/HAS2 positive feedback loop promotes EMT in breast cancer.
abstract: Cancer metastasis is the main reason for poor patient survival. Tumor cells delaminate from the primary tumor by induction of epithelial-mesenchymal transition (EMT). EMT is mediated by key transcription factors, including ZEB1, activated by tumor cell interactions with stromal cells and the extracellular matrix (ECM). ZEB1-mediated EMT and motility is accompanied by substantial cell reprogramming and the acquisition of a stemness phenotype. However, understanding of the underlying mechanism is still incomplete. We identified hyaluronic acid (HA), one major ECM proteoglycan and enriched in mammary tumors, to support EMT and enhance ZEB1 expression in cooperation with CD44s. In breast cancer cell lines HA is synthesized mainly by HAS2, which was already shown to be implicated in cancer progression. ZEB1 and HAS2 expression strongly correlates in various cancer entities and high HAS2 levels associate with an early relapse. We identified HAS2, tumor cell-derived HA and ZEB1 to form a positive feedback loop as ZEB1, elevated by HA, directly activates HAS2 expression. In an in vitro differentiation model HA-conditioned medium of breast cancer cells is enhancing osteoclast formation, an indicator of tumor cell-induced osteolysis that facilitates formation of bone metastasis. In combination with the previously identified ZEB1/ESRP1/CD44s feedback loop, we found a novel autocrine mechanism how ZEB1 is accelerating EMT.
authors.affiliation: Department of General and Visceral Surgery, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Bogdan-Tiberius
authors.initials: BT
authors.lastname: Preca
authors.affiliation: Department of General and Visceral Surgery, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
authors.forename: Karolina
authors.initials: K
authors.lastname: Bajdak
authors.affiliation: Department of General and Visceral Surgery, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Mock
authors.affiliation: Department of General and Visceral Surgery, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
authors.forename: Waltraut
authors.initials: W
authors.lastname: Lehmann
authors.affiliation: Department of General and Visceral Surgery, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
authors.forename: Vignesh
authors.initials: V
authors.lastname: Sundararajan
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany.|Institute for Surgical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany.|Tumorbank Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bronsert
authors.affiliation: Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, Eggenstein-Leopoldshafen, Germany.|Amcure GmbH, Eggenstein-Leopoldshafen, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Matzge-Ogi
authors.affiliation: Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, Eggenstein-Leopoldshafen, Germany.
authors.forename: Véronique
authors.initials: V
authors.lastname: Orian-Rousseau
authors.affiliation: Department of Experimental Medicine I, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of 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, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brabletz
authors.affiliation: Department of General and Visceral Surgery, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Maurer
authors.affiliation: Department of Experimental Medicine I, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Stemmler
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004797:Enzyme-Linked Immunosorbent Assay; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D025461:Feedback, Physiological / Q000502:physiology; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D000076002:Hyaluronan Synthases; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D009361:Neoplasm Invasiveness / Q000473:pathology; D010010:Osteoclasts / Q000473:pathology; D016133:Polymerase Chain Reaction; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000378:metabolism*
chemical_list: C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D014453:Glucuronosyltransferase; C101754:HAS2 protein, human; D000076002:Hyaluronan Synthases
keywords: CD44 signaling; epithelial-mesenchymal transition; hyaluronic acid synthase 2 (HAS2); invasion; metastasis