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© The Rockefeller University Press, 0021-9525/1998//159 $5.00
The Journal of Cell Biology, Volume 140, Number 1, , 1998 159-169

Article

Epimorphin Functions as a Key Morphoregulator for Mammary Epithelial Cells



Yohei Hirai*,{ddagger}, André Lochter*, Sybille Galosy*, Shogo Koshida{ddagger}, Shinichiro Niwa{ddagger}, and Mina J. Bissell*

* Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720; and {ddagger} Biomedical Research and Development Department, Sumitomo Electric Industries, Ltd., Yokohama 244, Japan

Hepatocyte growth factor (HGF) and EGF have been reported to promote branching morphogenesis of mammary epithelial cells. We now show that it is epimorphin that is primarily responsible for this phenomenon. In vivo, epimorphin was detected in the stromal compartment but not in lumenal epithelial cells of the mammary gland; in culture, however, a subpopulation of mammary epithelial cells produced significant amounts of epimorphin. When epimorphin-expressing epithelial cell clones were cultured in collagen gels they displayed branching morphogenesis in the presence of HGF, EGF, keratinocyte growth factor, or fibroblast growth factor, a process that was inhibited by anti-epimorphin but not anti-HGF antibodies. The branch length, however, was roughly proportional to the ability of the factors to induce growth. Accordingly, epimorphin-negative epithelial cells simply grew in a cluster in response to the growth factors and failed to branch. When recombinant epimorphin was added to these collagen gels, epimorphin-negative cells underwent branching morphogenesis. The mode of action of epimorphin on morphogenesis of the gland, however, was dependent on how it was presented to the mammary cells. If epimorphin was overexpressed in epimorphin-negative epithelial cells under regulation of an inducible promoter or was allowed to coat the surface of each epithelial cell in a nonpolar fashion, the cells formed globular, alveoli-like structures with a large central lumen instead of branching ducts. This process was enhanced also by addition of HGF, EGF, or other growth factors and was inhibited by epimorphin antibodies. These results suggest that epimorphin is the primary morphogen in the mammary gland but that growth factors are necessary to achieve the appropriate cell numbers for the resulting morphogenesis to be visualized.

Abbreviations used in this paper: ECM, extracellular matrix; HGF and KGF, hepatocyte and keratinocyte growth factor.

Address all correspondence to Yohei Hirai, Lawrence Berkeley National Laboratory, Life Science Division, One Cyclotron Road, MS 83-101, Berkeley, CA 94720. Tel.: (510) 486-4368. Fax: (510) 486-5586. E-mail: yhirai{at}lbl.gov

A. Lochter's present address is Center for Clinical and Basic Research, 222 Ballerup Byvej, DK-2750, Ballerup, Denmark.


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