Tumour-stromal interactions. Role of the stroma in mammary development

Mammary development depends on branching morphogenesis, namely the bifurcation and extension of ductal growth points (end buds) and secretory lobules into a more or less fatty stroma. Because breast carcinomas are overwhelmingly ductal in origin, this review focuses on stromal influences guiding postnatal ductal development and there is only the briefest account of the role of embryonic stroma (mesenchyme). The stroma as the necessary target for endocrine mammogens and the source of stimulatory growth factors is described and the importance of mammary epithelium-induced modifications of the periductal stroma is emphasized. Evidence is presented that if they are to grow, end buds must condition proximal fatty stroma by recruiting white blood cells as well as inducing stromal cell division and, possibly, estrogen receptors. The induction of a fibrous stromal tunic around the end bud is described and its likely role as a complex ductal morphogen is discussed; a possible role in growth inhibition is also considered. Although the signals governing fibrotic induction, ductal morphogenesis, and growth inhibition are unknown, a role for transforming growth factor-beta is highly likely and is discussed. Finally, a need for new conceptual and experimental approaches to understanding stromal-epithelial signaling is discussed.