title: Sustained activation of the HER1-ERK1/2-RSK signaling pathway controls myoepithelial cell fate in human mammary tissue.
abstract: Human mammary glands arise from multipotent progenitor cells, which likely respond both to cell-autonomous and to extrinsic cues. However, the identity of these cues and how they might act remain unclear. We analyzed HER1 ligand effects on mammary morphogenesis using a three-dimensional organoid model generated from human breast tissue that recapitulates both qualitatively and quantitatively the normal ductal network in situ. Strikingly, different HER1 ligands generate distinct patterns of cell fate. Epidermal growth factor (EGF) causes a massive expansion of the myoepithelial lineage. Amphiregulin, in contrast, enables normal ductal development. These differences cannot be ascribed to preferential apoptosis or proliferation of differentiated cell populations, but are dependent on HER1 signal intensity. Inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2) effector RSK prevents the EGF-induced myoepithelial expansion. Notably, mouse mammary organoids are much less responsive to HER1 ligands. Little is known about the myoepithelial lineage or about growth factor effects on mammary progenitor differentiation, and our studies provide an important window into human mammary development that reveals unexpected differences from the mouse model.
authors.affiliation: Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Lejla
authors.initials: L
authors.lastname: Pasic
authors.forename: T S Karin
authors.initials: TS
authors.lastname: Eisinger-Mathason
authors.forename: Bisi T
authors.initials: BT
authors.lastname: Velayudhan
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Moskaluk
authors.forename: David R
authors.initials: DR
authors.lastname: Brenin
authors.forename: Ian G
authors.initials: IG
authors.lastname: Macara
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Lannigan
mesh_terms: D066258:Amphiregulin; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016667:Bacterial Capsules / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D006023:Glycoproteins / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D042361:Mammary Glands, Human / Q000166:cytology / Q000187:drug effects / Q000254:growth & development*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C039514:capsular polysaccharide K14; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D051497:Receptor, Fibroblast Growth Factor, Type 2; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3