The mammary epithelium develops in an ongoing, hormonally driven process that occurs throughout reproductive life. At the onset of puberty, epithelial invasion into the mammary fat pad accelerates dramatically and over the next seven weeks the epithelial network expands dramatically in size and complexity. The mammary epithelium continues to remodel during normal hormonal cycles and during each pregnancy, lactation, and involution cycle. In addition, the mammary gland is capable of extensive regeneration, as isolated fragments of epithelium, or even a single mammary stem cell can regenerate a complete epithelial network with all functional lineages are capable of regenerating.. During puberty, terminal end buds (TEBs) form transiently at the end of each primary duct. TEBs are characteristically different from quiescent ducts, with multiple luminal cell layers enriched in mammary stem cells that increase during puberty and high levels of proliferation. The multilayered TEB gives rise to bilayered ducts, with myoepithelial cells surrounding luminal epithelial cells. Using confocal time-lapse imaging, we showed that mammary epithelium first reorganizes into a multilayered, highly proliferative, incompletely polarized state. New ducts initiate from these preinvasive structures in a Rac- and myosin light chain kinase-dependent fashion. Cells in elongating ducts dynamically rearrange and lack leading cellular extensions. We also found that mammary branching morphogenesis results from the coordinate motility of two different cell types: luminal and myoepithelial cells. They move differently, and the myoepithelial cells appeared to restrain advancing luminal ducts. Importantly, organotypic cultures from normal human breast show the same behavior, indicating that the basic principles underlying breast development are used in both mouse and humans. Because the organization of normal terminal end buds, mammary hyperplasias, and ducts in organotypic culture are similar, suggesting that common cellular mechanisms may underlie normal pubertal development and neoplastic epithelial morphogenesis.
Supported by funds from the National Institute of Environmental Heath Sciences and the National Cancer Institute (ES012801 and CA057621)