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Epimorphin Functions as a Key Morphoregulator for Mammary Epithelial Cells

Journal Article · · Journal of Cell Biology
 [1];  [2];  [2];  [3];  [3];  [2]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Science Division; Sumitomo Electric Industries, Yokohama (Japan). Biomedical Research and Development Dept.; DOE/OSTI
  2. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Science Division
  3. Sumitomo Electric Industries, Yokohama (Japan). Biomedical Research and Development Dept.
Hepatocyte growth factor (HGF) and EGF have been reported to promote branching morphogenesis of mammary epithelial cells. We now show that it is epimorphin that is primarily responsible for this phenomenon. In vivo, epimorphin was detected in the stromal compartment but not in lumenal epithelial cells of the mammary gland; in culture, however, a subpopulation of mammary epithelial cells produced significant amounts of epimorphin. When epimorphin-expressing epithelial cell clones were cultured in collagen gels they displayed branching morphogenesis in the presence of HGF, EGF, keratinocyte growth factor, or fibroblast growth factor, a process that was inhibited by anti-epimorphin but not anti-HGF antibodies. The branch length, however, was roughly proportional to the ability of the factors to induce growth. Accordingly, epimorphin-negative epithelial cells simply grew in a cluster in response to the growth factors and failed to branch. When recombinant epimorphin was added to these collagen gels, epimorphin-negative cells underwent branching morphogenesis. The mode of action of epimorphin on morphogenesis of the gland, however, was dependent on how it was presented to the mammary cells. If epimorphin was overexpressed in epimorphin-negative epithelial cells under regulation of an inducible promoter or was allowed to coat the surface of each epithelial cell in a nonpolar fashion, the cells formed globular, alveoli-like structures with a large central lumen instead of branching ducts. This process was enhanced also by addition of HGF, EGF, or other growth factors and was inhibited by epimorphin antibodies. These results suggest that epimorphin is the primary morphogen in the mammary gland but that growth factors are necessary to achieve the appropriate cell numbers for the resulting morphogenesis to be visualized.
Research Organization:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1625107
Journal Information:
Journal of Cell Biology, Journal Name: Journal of Cell Biology Journal Issue: 1 Vol. 140; ISSN 0021-9525
Publisher:
Rockefeller University PressCopyright Statement
Country of Publication:
United States
Language:
English

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Matrix Metalloproteinase-Induced Epithelial-Mesenchymal Transition in Breast Cancer journal May 2010
Angiotensin stimulation of adrenal fasciculata cells journal July 1988
Epimorphin acts extracellularly to promote cell sorting and aggregation during the condensation of vertebral cartilage journal March 2006
The MAPKERK-1,2 pathway integrates distinct and antagonistic signals from TGFα and FGF7 in morphogenesis of mouse mammary epithelium journal June 2007
The metastasis-promoting protein S100A4 regulates mammary branching morphogenesis journal April 2011
PI3K regulates branch initiation and extension of cultured mammary epithelia via Akt and Rac1 respectively journal July 2013
Cell–Cell Adhesion Molecule CEACAM1 is Expressed in Normal Breast and Milk and Associates with β1 Integrin in a 3D Model of Morphogenesis journal March 2003
Membrane translocation of t-SNARE protein syntaxin-4 abrogates ground-state pluripotency in mouse embryonic stem cells journal January 2017
EGF controls the in vivo developmental potential of a mammary epithelial cell line possessing progenitor properties journal November 2002
Epimorphin expression in interstitial pneumonia journal January 2005
Myoepithelial cells: good fences make good neighbors journal July 2005
42nd Annual Meeting of the American Society for Cell Biology, San Francisco, California, USA, 14–18 December 2002 journal June 2003
Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes journal February 2003
Retinoids induce lumen morphogenesis in mammary epithelial cells journal December 2002
Epimorphin Regulates Bile Duct Formation via Effects on Mitosis Orientation in Rat Liver Epithelial Stem-Like Cells journal March 2010
Epimorphin-Induced MET Sensitizes Ovarian Cancer Cells to Platinum journal September 2013
Engineering Three-dimensional Epithelial Tissues Embedded within Extracellular Matrix journal July 2016
Membrane‐tethered syntaxin‐4 locally abrogates E‐cadherin function and activates Smad signals, contributing to asymmetric mammary epithelial morphogenesis journal May 2018
Colonic subepithelial myofibroblasts in mucosal inflammation and repair: contribution of bone marrow-derived stem cells to the gut regenerative response journal December 2005
Epithelial Progenitors in the Normal Human Mammary Gland journal January 2005
Constructing Three-Dimensional Models to Study Mammary Gland Branching Morphogenesis and Functional Differentiation journal May 2012
Characterization of bipotent mammary epithelial progenitor cells in normal adult human breast tissue journal May 2001
Modelling glandular epithelial cancers in three-dimensional cultures journal September 2005
Nuclear repartitioning of galectin-1 by an extracellular glycan switch regulates mammary morphogenesis journal August 2016
Signaling Properties of Hyaluronan Receptors journal February 2002
Autocrine Stimulation of Human Pancreatic Duct–Like Development by Soluble Isoforms of Epimorphin in Vitro journal February 2001
Tenascin‐C and SF/HGF produced by myofibroblasts in vitro provide convergent proinvasive signals to human colon cancer cells through RhoA and Rac journal April 2004
Morphogenic protein epimorphin protects intestinal epithelial cells from oxidative stress by the activation of EGF receptor and MEK/ERK, PI3 kinase/Akt signals journal January 2007
SNARE expression and localization in renal epithelial cells suggest mechanism for variability of trafficking phenotypes journal November 2002
Epimorphin expression in intestinal myofibroblasts induces epithelial morphogenesis journal December 2002
Extracellularly Extruded Syntaxin-4 Is a Potent Cornification Regulator of Epidermal Keratinocytes journal January 2015

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