Mammary glands develop postnatally by branching morphogenesis creating an arborated ductal system on which secretory lobuloalveoli develop at pregnancy. This review focuses on the interrelated questions of how ductal and alveolar morphogenesis and growth are regulated in the mouse mammary gland and covers progress made over approximately the last decade. After a brief overview of glandular development, advances in understanding basic structural questions concerning mechanisms of duct assembly, elongation, and bifurcation are considered. Turning to growth regulation, remarkable progress has taken place based largely on the study of genetically engineered mice that lack or overexpress a single gene. The use of mammary glands from these and wildtype animals in sophisticated epithelial-stromal or epithelial-epithelial recombination experiments are reviewed and demonstrate paracrine mechanisms of action for the classical endocrine mammogens, estrogen, progesterone, growth hormone, and prolactin. In addition, IGF-1, EGF, or related peptides, and elements of the activin/inhibin family, were shown to be necessary for ductal growth. The inhibition of ductal growth, and in particular, lateral branching, is necessary to preserve stromal space for later lobuloalveolar development. Excellent evidence that TGF-beta1 naturally inhibits this infilling, possibly by blocking hepatocyte growth factor synthesis, is reviewed along with evidence indicating that the action of TGF-beta1 is modulated by its association with the extracellular matrix. Finally, experimental approaches that may help integrate the wealth of new findings are discussed.
Copyright 2001 Wiley-Liss, Inc.