Sustained activation of the HER1-ERK1/2-RSK signaling pathway controls myoepithelial cell fate in human mammary tissue
Sustained activation of the HER1-ERK1/2-RSK signaling pathway controls myoepithelial cell fate in human mammary tissue
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DOI：
10.1101/gad.2025611
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发表时间：
2011-08-01
影响因子：
10.5
通讯作者：
Lannigan, Deborah A.
中科院分区：
文献类型：
--
作者：
Pasic, Lejla;Eisinger-Mathason, T. S. Karin;Lannigan, Deborah A.
人类乳腺起源于多能祖细胞，它们可能对细胞自主和外部提示做出反应。然而，这些线索的身份以及它们可能会如何行动仍不清楚。我们分析了HER1配体对乳腺形态发生的影响，使用从人的乳腺组织产生的三维器官模型，在原位定性和定量地概括了正常的导管网络。引人注目的是，不同的HER1配体会产生不同的细胞命运模式。表皮生长因子(EGF)导致肌上皮细胞系的大规模扩张。相比之下，双调蛋白能促进正常的导管发育。这些差异不能归因于分化细胞群体的优先凋亡或增殖，而是依赖于HER1信号强度。抑制细胞外信号调节激酶1/2(ERK1/2)效应器RSK可阻止EGF诱导的肌上皮细胞扩张。值得注意的是，小鼠乳腺器官对HER1配体的反应要小得多。目前对肌上皮细胞谱系或生长因子对乳腺祖细胞分化的影响知之甚少，我们的研究为了解人类乳腺发育提供了一个重要的窗口，揭示了与小鼠模型的意外差异。
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.