PMID- 26831618
OWN - NLM
STAT- MEDLINE
DCOM- 20170106
LR  - 20181202
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 6
DP  - 2016 Feb 2
TI  - Reversible interconversion and maintenance of mammary epithelial cell 
      characteristics by the ligand-regulated EGFR system.
PG  - 20209
LID - 10.1038/srep20209 [doi]
LID - 20209
AB  - Epithelial cell plasticity is controlled by extracellular cues, but the 
      underlying mechanisms remain to be fully understood. Epidermal growth factor 
      (EGF) and amphiregulin (AREG) are high- and low-affinity ligands for EGF receptor 
      (EGFR), respectively. EGFR signaling is known to promote epithelial-mesenchymal 
      transition (EMT) by the activation of ERK and the induction of an EMT 
      transcription factor, ZEB1. Here, we demonstrate that ligand-switching between 
      EGF and AREG at equivalent molarity reversibly interconverts epithelial and 
      mesenchymal-like states of EGFR signal-dependent mammary epithelial cells. The 
      EGF- and AREG-cultured cells also differ in their epithelial characteristics, 
      including the expression of cell surface markers, the mode of migration and the 
      ability for acinus-formation. The ligand-switching between EGF and AREG 
      temporally alters strength of the shared EGFR-ERK signaling. This alteration 
      inverts relative expression levels of ZEB1 and its antagonizing microRNAs, 
      miR-205 and miR-200c, those are critical determinants of the epithelial 
      phenotype. Further, AREG-induced EGFR accumulation on the plasma membrane 
      compensates for the weak association between AREG and EGFR. The EGFR dynamics 
      enables AREG to support proliferation as efficiently as EGF at equivalent 
      molarity and to maintain epithelial characteristics. Our findings reveal a role 
      of EGFR ligands-generated signal strength in the regulation of mammary epithelial 
      cell plasticity.
FAU - Fukuda, Shinji
AU  - Fukuda S
AD  - Division of Cell Growth and Tumor Regulation, Proteo-Science Center (PROS), Ehime 
      University, Toon, Ehime, Japan.
AD  - Department of Biochemistry and Molecular Genetics, Ehime University Graduate 
      School of Medicine, Toon, Ehime, Japan.
FAU - Nishida-Fukuda, Hisayo
AU  - Nishida-Fukuda H
AD  - Department of Biochemistry and Molecular Genetics, Ehime University Graduate 
      School of Medicine, Toon, Ehime, Japan.
FAU - Nanba, Daisuke
AU  - Nanba D
AD  - Division of Cell Growth and Tumor Regulation, Proteo-Science Center (PROS), Ehime 
      University, Toon, Ehime, Japan.
AD  - Department of Biochemistry and Molecular Genetics, Ehime University Graduate 
      School of Medicine, Toon, Ehime, Japan.
FAU - Nakashiro, Koh-ichi
AU  - Nakashiro K
AD  - Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of 
      Medicine, Toon, Ehime, Japan.
FAU - Nakayama, Hironao
AU  - Nakayama H
AD  - Division of Cell Growth and Tumor Regulation, Proteo-Science Center (PROS), Ehime 
      University, Toon, Ehime, Japan.
AD  - Department of Biochemistry and Molecular Genetics, Ehime University Graduate 
      School of Medicine, Toon, Ehime, Japan.
FAU - Kubota, Hiroyuki
AU  - Kubota H
AD  - Division of Integrated Omics, Research Center for Transomics Medicine, Medical 
      Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
AD  - PRESTO, Japan Science and Technology Corporation, Fukuoka, Japan.
FAU - Higashiyama, Shigeki
AU  - Higashiyama S
AD  - Division of Cell Growth and Tumor Regulation, Proteo-Science Center (PROS), Ehime 
      University, Toon, Ehime, Japan.
AD  - Department of Biochemistry and Molecular Genetics, Ehime University Graduate 
      School of Medicine, Toon, Ehime, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160202
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (AREG protein, human)
RN  - 0 (Amphiregulin)
RN  - 0 (Ligands)
RN  - 0 (Transforming Growth Factor beta)
RN  - 62229-50-9 (Epidermal Growth Factor)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Amphiregulin/metabolism
MH  - Breast Neoplasms/genetics/metabolism/pathology
MH  - Cell Line, Tumor
MH  - Epidermal Growth Factor/metabolism
MH  - Epithelial Cells/*metabolism/pathology
MH  - Epithelial-Mesenchymal Transition/genetics
MH  - ErbB Receptors/*metabolism
MH  - Female
MH  - Gene Expression Regulation
MH  - Humans
MH  - *Ligands
MH  - MAP Kinase Signaling System
MH  - Mammary Glands, Human/*cytology/*metabolism/pathology
MH  - Phenotype
MH  - Phosphorylation
MH  - Signal Transduction
MH  - Transforming Growth Factor beta/metabolism
PMC - PMC4735799
EDAT- 2016/02/03 06:00
MHDA- 2017/01/07 06:00
PMCR- 2016/02/02
CRDT- 2016/02/03 06:00
PHST- 2015/09/08 00:00 [received]
PHST- 2015/12/23 00:00 [accepted]
PHST- 2016/02/03 06:00 [entrez]
PHST- 2016/02/03 06:00 [pubmed]
PHST- 2017/01/07 06:00 [medline]
PHST- 2016/02/02 00:00 [pmc-release]
AID - srep20209 [pii]
AID - 10.1038/srep20209 [doi]
PST - epublish
SO  - Sci Rep. 2016 Feb 2;6:20209. doi: 10.1038/srep20209.