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

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KOLEDOVÁ Zuzana ZHANG Xiaohong STREULI Charles CLARKE Robert B. KLEIN Ophir D. WERB Zena LU Pengfei

Year of publication 2016
Type Article in Periodical
Magazine / Source Proceedings of the National Academy of Sciences of the United States of America
MU Faculty or unit

Faculty of Medicine

Field Genetics and molecular biology
Keywords branching morphogenesis; FGF signaling; EGF signaling; epithelial-stromal interactions; stromal microenvironment
Description 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 themutant 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.
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