SPRY1 regulates mammary epithelial morphogenesis by modulating EGFR-dependent stromal paracrine signaling and ECM remodeling.
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.
Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom; Wellcome Trust Centre for Cell Matrix Research, University of Manchester, Manchester M13 9PT, United Kingdom; Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno 62500, Czech Republic; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China;
Zuzana
Z
Koledova
Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom; Wellcome Trust Centre for Cell Matrix Research, University of Manchester, Manchester M13 9PT, United Kingdom;
Xiaohong
X
Zhang
Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom; Wellcome Trust Centre for Cell Matrix Research, University of Manchester, Manchester M13 9PT, United Kingdom;
Charles
C
Streuli
Breast Cancer Now Research Unit, Institute of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester M20 4QL, United Kingdom;
Robert B
RB
Clarke
Department of Orofacial Sciences, University of California, San Francisco, CA 94143; Department of Pediatrics, University of California, San Francisco, CA 94143; Program in Craniofacial Biology, University of California, San Francisco, CA 94143; Institute for Human Genetics, University of California, San Francisco, CA 94143;
Ophir D
OD
Klein
Department of Anatomy, University of California, San Francisco, CA 94143 lvpf@shanghaitech.edu.cn zena.werb@ucsf.edu.
Zena
Z
Werb
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; lvpf@shanghaitech.edu.cn zena.werb@ucsf.edu.
Pengfei
P
Lu
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism*; D066258:Amphiregulin / Q000494:pharmacology; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D004848:Epithelium / Q000254:growth & development* / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D008024:Ligands; D008297:Male; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D018345:Mice, Knockout; D008819:Mice, Nude; D009024:Morphogenesis / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D019899:Paracrine Communication / Q000187:drug effects; D010750:Phosphoproteins / Q000172:deficiency / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D059008:Time-Lapse Imaging; D016211:Transforming Growth Factor alpha / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D066258:Amphiregulin; D008024:Ligands; D008565:Membrane Proteins; D010750:Phosphoproteins; C425468:Spry1 protein, mouse; D016211:Transforming Growth Factor alpha; D003094:Collagen; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
EGF signaling; FGF signaling; branching morphogenesis; epithelial–stromal interactions; stromal microenvironment