Roles of Hepatocyte Growth Factor/Scatter Factor and Transforming Growth Factor-β1 in Mammary Gland Ductal Morphogenesis

Epithelial-mesenchymal interactions areresponsible for the unique pattern of ductal branchingmorphogenesis characteristic of the mammary gland. Toinvestigate the factors which control the elongation and branching of lactiferous ducts, wedeveloped an in vitro model of ductal morphogenesis inwhich clonal mouse mammary epithelial cells (TAC-2cells) are grown in collagen gels. In this experimentalsystem, fibroblast conditioned medium (CM)3stimulates the formation of extensively arborizedtubules. The molecule responsible for this tubulogeniceffect was identified as hepatocyte growthfactor/scatter factor (HGF/SF). To determine whether HGF/SF plays arole in mammary gland morphogenesis in vivo, theexpression of HGF/SF and its receptor, cMet, wereanalyzed in the rat mammary gland during pregnancy,lactation, and involution. Levels of HGF/SF and c-Mettranscripts were progressively reduced during pregnancy,were virtually undetectable during lactation, andincreased again during involution. Collectively, these in vitro and in vivo findings suggest thatHGF/SF is a paracrine mediator of mammary gland ductalmorphogenesis. We subsequently investigated the effectof another multifunctional cytokine, namely TGF-beta1, on branching morphogenesis of TAC-2 cells.TGF-β1 had a striking biphasic effect:whereas relatively high concentrations of this cytokineinhibited colony formation, lower concentrationsstimulated extensive elongation and branching of epithelial cords.Taken together, these studies indicate that HGF/SF is astromal-derived paracrine mediator of mammary ductalmorphogenesis, and that when present at lowconcentrations, TGF-β1 can contribute to thisprocess.