Journal Article

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

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

2016

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Adaptor Proteins, Signal Transducing - deficiency / Adaptor Proteins, Signal Transducing - metabolism / Amphiregulin - pharmacology / Animals / Biological Sciences / Cancer / Cell Movement - drug effects / Cellular biology / Collagen - metabolism / Developmental Biology / Epidermal growth factor / Epithelial Cells - cytology / Epithelial Cells - drug effects / Epithelium - growth & development / Epithelium - metabolism / ErbB Receptors - metabolism / Extracellular Matrix - metabolism / Extracellular Signal-Regulated MAP Kinases - metabolism / Female / Fibroblasts - drug effects / Fibroblasts - metabolism / Gene Expression Regulation, Developmental - drug effects / Kinases / Ligands / Male / Mammary Glands, Animal - drug effects / Mammary Glands, Animal - metabolism / Membrane Proteins - deficiency / Membrane Proteins - metabolism / Mice, Knockout / Mice, Nude / Morphogenesis / Morphogenesis - drug effects / Mutation / Mutation - genetics / Paracrine Communication - drug effects / Phosphoproteins - deficiency / Phosphoproteins - metabolism / Phosphorylation - drug effects / PNAS Plus / Proto-Oncogene Proteins c-akt - metabolism / Signal Transduction - drug effects / Stromal Cells - drug effects / Stromal Cells - metabolism / Time-Lapse Imaging / Transforming Growth Factor alpha - pharmacology