Signaling through the stromal epidermal growth factor receptor is necessary for mammary ductal development

Stromal-epithelial interactions are critical in determining patterns of gro wth, development and ductal morphogenesis in the mammary gland, and their p erturbations are significant components of tumorigenesis, Growth factors su ch as epidermal growth factor (EGF) contribute to these reciprocal stromal- epithelial interactions. To determine the role of signaling through the EGF receptor (EGFR) in mammary ductal growth and branching, we used mice with a targeted null mutation in the Egfr, Because Egfr(-/-) mice die perinatall y, transplantation methods were used to study these processes. When we tran splanted neonatal mammary glands under the renal capsule of immune-compromi sed female mice, we found that EGFR is essential for mammary ductal growth and branching morphogenesis, but not for mammary lobulo-alveolar developmen t. Ductal growth and development was normal in transplants of mammary epith elium from Egfr(-/-) mice into wild-type (WT) gland-free fat pads and in ti ssue recombinants prepared with WT stroma, irrespective of the source of ep ithelium (Stroma(WT)/Epi(-/-), Stroma(WT)/Epi(WT)). However, ductal growth and branching was impaired in tissue recombinants prepared with Egfr(-/-) s troma (Stroma(-/-)/Epi(WT), Stroma(-/-)/Epi(-/-)). Thus, for ductal morphog enesis, signaling through the EGFR is required only in the stromal componen t, the mammary fat pad. These data indicate that the EGFR pathway plays a k ey role in the stromal-epithelial interactions required for mammary ductal growth and branching morphogenesis, In contrast, signaling through the EGFR is not essential for lobulo-alveolar development. Stimulation of lobulo-al veolar development in the mammary gland grafts by inclusion of a pituitary isograft under the renal capsule as a source of prolactin resulted in norma l alveolar development in both Egfr(-/-) and wild-type transplants. Through the use of tissue recombinants and transplantation, we have gained new ins ights into the nature of stromal-epithelial interactions in the mammary gla nd, and how they regulate ductal growth and branching morphogenesis.