title: Reversible interconversion and maintenance of mammary epithelial cell characteristics by the ligand-regulated EGFR system.
abstract: 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.
authors.affiliation: Division of Cell Growth and Tumor Regulation, Proteo-Science Center (PROS), Ehime University, Toon, Ehime, Japan.|Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Fukuda
authors.affiliation: Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: Hisayo
authors.initials: H
authors.lastname: Nishida-Fukuda
authors.affiliation: Division of Cell Growth and Tumor Regulation, Proteo-Science Center (PROS), Ehime University, Toon, Ehime, Japan.|Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nanba
authors.affiliation: Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: Koh-ichi
authors.initials: K
authors.lastname: Nakashiro
authors.affiliation: Division of Cell Growth and Tumor Regulation, Proteo-Science Center (PROS), Ehime University, Toon, Ehime, Japan.|Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: Hironao
authors.initials: H
authors.lastname: Nakayama
authors.affiliation: Division of Integrated Omics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.|PRESTO, Japan Science and Technology Corporation, Fukuoka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kubota
authors.affiliation: Division of Cell Growth and Tumor Regulation, Proteo-Science Center (PROS), Ehime University, Toon, Ehime, Japan.|Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Higashiyama
mesh_terms: D066258:Amphiregulin / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008024:Ligands; D020935:MAP Kinase Signaling System; D042361:Mammary Glands, Human / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D008024:Ligands; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; D066246:ErbB Receptors
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