Sustained activation of the HER1-ERK1/2-RSK signaling pathway controls myoepithelial cell fate in human mammary tissue.

Pasic L, Eisinger-Mathason TS, Velayudhan BT, Moskaluk CA, Brenin DR, Macara IG, Lannigan DA
Genes Dev. 2011 25 (15): 1641-53

PMID: 21828273 · PMCID: PMC3182019 · DOI:10.1101/gad.2025611

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.

MeSH Terms (21)

Amphiregulin Animals Apoptosis Bacterial Capsules Cell Differentiation Cell Proliferation Cells, Cultured EGF Family of Proteins Epidermal Growth Factor Epithelial Cells ErbB Receptors Glycoproteins Humans Intercellular Signaling Peptides and Proteins Mammary Glands, Human Mice Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Receptor, Fibroblast Growth Factor, Type 2 Ribosomal Protein S6 Kinases, 90-kDa Signal Transduction

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