SPRY1 regulates mammary epithelial morphogenesis by modulating EGFR-dependent stromal paracrine signaling and ECM remodeling

Zuzana Koledova, Xiaohong Zhang, Charles Streuli, Robert B Clarke, Ophir D Klein, Zena Werb, Pengfei Lu

Research output: Contribution to journalArticlepeer-review

Abstract

The role of the local microenvironment in influencing cell behavior is central to both normal development and cancer formation. Here, we show that sprouty 1 (SPRY1) modulates the microenvironment to enable proper mammary branching morphogenesis. This process occurs through negative regulation of epidermal growth factor receptor (EGFR) signaling in mammary stroma. Loss of SPRY1 resulted in up-regulation of EGFR-extracellular signal-regulated kinase (ERK) signaling in response to amphiregulin and transforming growth factor alpha stimulation. Consequently, stromal paracrine signaling and ECM remodeling is augmented, leading to increased epithelial branching in the mutant gland. By contrast, down-regulation of EGFR-ERK signaling due to gain of Sprouty function in the stroma led to stunted epithelial branching. Taken together, our results show that modulation of stromal paracrine signaling and ECM remodeling by SPRY1 regulates mammary epithelial morphogenesis during postnatal development.

Original languageEnglish
Pages (from-to)E5731-E5740
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number39
Early online date12 Sept 2016
DOIs
Publication statusPublished - 12 Sept 2016

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