Editorial: The Mammary Stroma in Normal Development and Function

The mammary gland can no longer be simply viewed as an organ composed of epithelial cells within a passive stromal microenvironment. Many lines of evidence have evolved to reinforce the notion that mammary epithelial cell growth, differentiation, lactation and progression to cancer involves bidirectional interactions between the epithelial population and its surrounding stroma. Within this stroma are numerous systems that are all capable of modulating epithelial function. In this context, the mammary stroma is not simply a depot of adipose tissue in which mammary epithelial cells undertake a unique growth and differentiation process, although adipocytes can impart numerous modulatory signals to epithelial cells, and vice versa. Rather, the stromal environment constitutes and supports a critical vasculature that supplies nutrients and endocrine cues, a lymphatic system that not only removes metabolites but also provides an intimate interface with the immune system, and an extracellular matrix scaffold in which epithelial cells grow, differentiate and regress. Ultimately all of these components play a critical role in directing the epithelial phenotype during normal mammary gland growth and function. An increasing appreciation for these different systems demands a view of mammary epithelial cells in a much different light, and further necessitates the development of model systems that incorporate and integrate increasing complexity

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

In order to fulfill its function of producing and delivering sufficient milk to newborn mammalian offspring, the mammary gland first has to form an extensive ductal network. As in all phases of mammary development, hormonal cues elicit local intra- and inter-cellular signaling cascades that regulate ductal growth and differentiation. Among other things, ductal development requires the epidermal growth factor receptor (EGFR), its ligand amphiregulin (AREG), and the transmembrane metalloproteinase AD-AM17, which can cleave and release AREG from the cell surface so that it may interact with its receptor. Tissue recombination and transplantation studies demonstrate that EGFR phosphorylation and ductal development proceed only when ADAM17 and AREG are expressed on mammary epithelial cells and EGFR is present on stromal cells, and that local administration of soluble AREG can rescue the development of ADAM17-deficient transplants. Thus proper mammary morphogenesis requires the ADAM17-mediated release of AREG from ductal epithelial cells, the subsequent activation of EGFR on stromal cells, and EGFR-dependent stromal responses that in return elicit a new set of epithelial responses, all culminating in the formation of a fully functional ductal tree. This, however, raises new issues concerning what may act upstream, downstream or in parallel with the ADAM17–AREG–EGFR axis, how it may become hijacked or corrupted during the onset and evolution of cancer, and how such ill effects may be confronted