Abstract
The mammary gland undergoes morphogenesis through the entire reproductive life of mammals. In mice, ductal outgrowth from the nipple across the fat pad results in an intricate, well spaced ductal tree that further ramifies and develops alveolar structures during pregnancy. Ductal morphogenesis is regulated by the concerted action of circulating steroid and polypeptide hormones, and local epithelial-mesenchymal inductive signals. Transforming growth factor (TGF)-β1-3 and hepatocyte growth factor (HGF)/scatter factor (SF) are important components of this latter signaling pathway. TGF-β1 and TGF-β3 have roles in both promotion and inhibition of branching morphogenesis that are dependent on concentration and context. HGF/SF promotes ductal outgrowth and tubule formation in the mammary gland. These data suggest that these two growth factors have complementary roles in promoting mammary ductal morphogenesis and in maintaining ductal spacing. In addition, TGF-β3 triggers apoptosis in the alveolar epithelia, which is a necessary component of mammary gland involution and return of the ductal structure to a virgin-like state after lactation.
Highlights
The development of the mammary gland largely occurs postnatally
Transforming growth factor (TGF)-βs might promote the outgrowth of terminal end buds (TEBs) and lateral branches at low concentration, whereas higher concentrations suppress growth in terminal end ducts and along the ductal length, perhaps by inhibiting expression or action of hepatocyte growth factor (HGF)/scatter factor (SF), as has been reported in culture [23] (Fig. 2)
HGF/SF is synthesized in the mammary stroma, probably by fibroblasts, and acts on receptor-expressing ductal epithelial cells [23]. Together these experiments strongly suggest that HGF/SF c-met signaling is a classical epithelial–mesenchymal inductive pathway that is important for ductal morphogenesis in the mammary gland (Fig. 2)
Summary
The development of the mammary gland largely occurs postnatally. Initially, the ductal system begins to develop from the nipple, and is characterized by specialized structures — the terminal end buds (TEBs) — capping the end of the ducts. TGF-βs might promote the outgrowth of TEBs and lateral branches at low concentration, whereas higher concentrations suppress growth in terminal end ducts and along the ductal length, perhaps by inhibiting expression or action of HGF/SF, as has been reported in culture [23] (Fig. 2) These conclusions would be consistent with the opposite effects on mammary development observed in mice with one or two mutant alleles of TGF-β1. Together these experiments strongly suggest that HGF/SF c-met signaling is a classical epithelial–mesenchymal inductive pathway that is important for ductal morphogenesis in the mammary gland (Fig. 2) Despite their dramatic nature, a caveat of the culture experiments is that the cells form unilaminar tubes that do not resemble the elaborate TEBs that are the primary growth point and determinant of branching in the developing mammary gland. These data are consistent with a positive role for HGF/SF in ductal morphogenesis (Fig. 2)
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