title: Loss of miR-203 regulates cell shape and matrix adhesion through ROBO1/Rac/FAK in response to stiffness.
abstract: Breast tumor progression is accompanied by changes in the surrounding extracellular matrix (ECM) that increase stiffness of the microenvironment. Mammary epithelial cells engage regulatory pathways that permit dynamic responses to mechanical cues from the ECM. Here, we identify a SLIT2/ROBO1 signaling circuit as a key regulatory mechanism by which cells sense and respond to ECM stiffness to preserve tensional homeostasis. We observed that Robo1 ablation in the developing mammary gland compromised actin stress fiber assembly and inhibited cell contractility to perturb tissue morphogenesis, whereas SLIT2 treatment stimulated Rac and increased focal adhesion kinase activity to enhance cell tension by maintaining cell shape and matrix adhesion. Further investigation revealed that a stiff ECM increased Robo1 levels by down-regulating miR-203. Consistently, patients whose tumor expressed a low miR-203/high Robo1 expression pattern exhibited a better overall survival prognosis. These studies show that cells subjected to stiffened environments up-regulate Robo1 as a protective mechanism that maintains cell shape and facilitates ECM adherence.
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064.
authors.forename: Lily Thao-Nhi
authors.initials: LT
authors.lastname: Le
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064.
authors.forename: Oscar
authors.initials: O
authors.lastname: Cazares
authors.affiliation: Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Janna K
authors.initials: JK
authors.lastname: Mouw
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064.
authors.forename: Sharmila
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064.
authors.forename: Hector
authors.initials: H
authors.lastname: Macias
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064.
authors.forename: Angel
authors.initials: A
authors.lastname: Moran
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064.
authors.forename: Jillian
authors.initials: J
authors.lastname: Ramos
authors.affiliation: Department of Cellular and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53706.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Keely
authors.affiliation: Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Weaver
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064 lhinck@ucsc.edu.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Hinck
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000235:genetics* / Q000502:physiology; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000235:genetics* / Q000502:physiology; D060833:Cellular Microenvironment / Q000235:genetics / Q000502:physiology; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000502:physiology; D005109:Extracellular Matrix / Q000235:genetics* / Q000502:physiology; D051417:Focal Adhesion Kinase 1 / Q000235:genetics*; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D042361:Mammary Glands, Human / Q000502:physiology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011971:Receptors, Immunologic / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D020744:rac GTP-Binding Proteins / Q000235:genetics*; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
chemical_list: D051417:Focal Adhesion Kinase 1; D036341:Intercellular Signaling Peptides and Proteins; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D020744:rac GTP-Binding Proteins; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C546703:MIRN203 microRNA, human; C496050:PTK2 protein, human