title: MicroRNA-200c-141 and ∆Np63 are required for breast epithelial differentiation and branching morphogenesis.
abstract: The epithelial compartment of the breast contains two lineages, the luminal- and the myoepithelial cells. D492 is a breast epithelial cell line with stem cell properties that forms branching epithelial structures in 3D culture with both luminal- and myoepithelial differentiation. We have recently shown that D492 undergo epithelial to mesenchymal transition (EMT) when co-cultured with endothelial cells. This 3D co-culture model allows critical analysis of breast epithelial lineage development and EMT. In this study, we compared the microRNA (miR) expression profiles for D492 and its mesenchymal-derivative D492M. Suppression of the miR-200 family in D492M was among the most profound changes observed. Exogenous expression of miR-200c-141 in D492M reversed the EMT phenotype resulting in gain of luminal but not myoepithelial differentiation. In contrast, forced expression of ∆Np63 in D492M restored the myoepithelial phenotype only. Co-expression of miR-200c-141 and ∆Np63 in D492M restored the branching morphogenesis in 3D culture underlining the requirement for both luminal and myoepithelial elements for obtaining full branching morphogenesis in breast epithelium. Introduction of a miR-200c-141 construct in both D492 and D492M resulted in resistance to endothelial induced EMT. In conclusion, our data suggests that expression of miR-200c-141 and ∆Np63 in D492M can reverse EMT resulting in luminal- and myoepithelial differentiation, respectively, demonstrating the importance of these molecules in epithelial integrity in the human breast.
authors.affiliation: Stem Cell Research Unit, Biomedical Center, Department of Anatomy, Faculty of Medicine, School of Health Sciences, University of Iceland, Iceland; Department of Laboratory Hematology, Landspitali-University Hospital, Iceland.
authors.forename: Bylgja
authors.initials: B
authors.lastname: Hilmarsdóttir
authors.affiliation: Stem Cell Research Unit, Biomedical Center, Department of Anatomy, Faculty of Medicine, School of Health Sciences, University of Iceland, Iceland; Department of Laboratory Hematology, Landspitali-University Hospital, Iceland.
authors.forename: Eirikur
authors.initials: E
authors.lastname: Briem
authors.affiliation: Stem Cell Research Unit, Biomedical Center, Department of Anatomy, Faculty of Medicine, School of Health Sciences, University of Iceland, Iceland.
authors.forename: Valgardur
authors.initials: V
authors.lastname: Sigurdsson
authors.affiliation: Stem Cell Research Unit, Biomedical Center, Department of Anatomy, Faculty of Medicine, School of Health Sciences, University of Iceland, Iceland.
authors.forename: Sigrídur Rut
authors.initials: SR
authors.lastname: Franzdóttir
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Ringnér
authors.affiliation: Stem Cell Research Unit, Biomedical Center, Department of Anatomy, Faculty of Medicine, School of Health Sciences, University of Iceland, Iceland; Department of Laboratory Hematology, Landspitali-University Hospital, Iceland.
authors.forename: Ari Jon
authors.initials: AJ
authors.lastname: Arason
authors.affiliation: Stem Cell Research Unit, Biomedical Center, Department of Anatomy, Faculty of Medicine, School of Health Sciences, University of Iceland, Iceland; Department of Laboratory Hematology, Landspitali-University Hospital, Iceland.
authors.forename: Jon Thor
authors.initials: JT
authors.lastname: Bergthorsson
authors.affiliation: Stem Cell Research Unit, Biomedical Center, Department of Anatomy, Faculty of Medicine, School of Health Sciences, University of Iceland, Iceland; Department of Laboratory Hematology, Landspitali-University Hospital, Iceland; Department of Medical Pharmacology and Toxicology, Faculty of Medicine, School of Health Sciences, University of Iceland, Iceland.
authors.forename: Magnus Karl
authors.initials: MK
authors.lastname: Magnusson
authors.affiliation: Stem Cell Research Unit, Biomedical Center, Department of Anatomy, Faculty of Medicine, School of Health Sciences, University of Iceland, Iceland; Department of Laboratory Hematology, Landspitali-University Hospital, Iceland. Electronic address: tgudjons@hi.is.
authors.forename: Thorarinn
authors.initials: T
authors.lastname: Gudjonsson
mesh_terms: D001940:Breast / Q000166:cytology* / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: C533896:MIRN200 microRNA, human; D035683:MicroRNAs
keywords: Breast cancer; Breast morphogenesis; EMT; MiR-200c-141; Stem cells; ∆Np63