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© The Rockefeller University Press, 0021-9525/1997//1861 $5.00
The Journal of Cell Biology, Volume 139, Number 7, , 1997 1861-1872

Article

Matrix Metalloproteinase Stromelysin-1 Triggers a Cascade of Molecular Alterations That Leads to Stable Epithelial-to-Mesenchymal Conversion and a Premalignant Phenotype in Mammary Epithelial Cells



André Lochter*, Sybille Galosy*, John Muschler*, Neal Freedman*, Zena Werb{ddagger}, and Mina J. Bissell*

* Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, California 94720; and {ddagger} Department of Anatomy, University of California, San Francisco, California 94143

Matrix metalloproteinases (MMPs) regulate ductal morphogenesis, apoptosis, and neoplastic progression in mammary epithelial cells. To elucidate the direct effects of MMPs on mammary epithelium, we generated functionally normal cells expressing an inducible autoactivating stromelysin-1 (SL-1) transgene. Induction of SL-1 expression resulted in cleavage of E-cadherin, and triggered progressive phenotypic conversion characterized by disappearance of E-cadherin and catenins from cell–cell contacts, downregulation of cytokeratins, upregulation of vimentin, induction of keratinocyte growth factor expression and activation, and upregulation of endogenous MMPs. Cells expressing SL-1 were unable to undergo lactogenic differentiation and became invasive. Once initiated, this phenotypic conversion was essentially stable, and progressed even in the absence of continued SL-1 expression. These observations demonstrate that inappropriate expression of SL-1 initiates a cascade of events that may represent a coordinated program leading to loss of the differentiated epithelial phenotype and gain of some characteristics of tumor cells. Our data provide novel insights into how MMPs function in development and neoplastic conversion.

Abbreviations used in this paper: DAPI, 4',6-diamidino-2-phenylindole; ECCD, antibody to the extracellular domain of E-cadherin; ECM, extracellular matrix; EMT, epithelial–mesenchymal transition; HGF, hepatocyte growth factor; KGF, keratinocyte growth factor; MMP, matrix metalloproteinase; RT, reverse transcription; SL-1, stromelysin-1; Tet, tetracycline; TGF-β, transforming growth factor–β; TIMP2, tissue inhibitor of metalloproteinases–2.

Address all correspondence to M.J. Bissell, Life Sciences Division, Building 83, Lawrence Berkeley National Laboratory, University of California, 1 Cyclotron Road, Berkeley, CA 94720. Tel.: (510) 486-4365. Fax: (510) 486-5586. E-mail: mjbissell{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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