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

Matrix metalloproteinases (MMPs) regulate ductal morphogenesis, apopto sis, and neoplastic progression in mammary epithelial cells. To elucid ate the direct effects of MMPs on mammary epithelium, we generated fun ctionally normal cells expressing an inducible autoactivating stromely sin-1 (SL-1) transgene. Induction of SL-1 expression resulted in cleav age of E-cadherin, and triggered progressive phenotypic conversion cha racterized by disappearance of E-cadherin and catenins from cell-cell contacts, downregulation of cytokeratins, upregulation of vimentin, in duction of keratinocyte growth factor expression and activation, and u pregulation of endogenous MMPs. Cells expressing SL-1 were unable to u ndergo lactogenic differentiation and became invasive. Once initiated, this phenotypic conversion was essentially stable, and progressed eve n in the absence of continued SL-1 expression. These observations demo nstrate that inappropriate expression of SL-1 initiates a cascade of e vents that may represent a coordinated program leading to loss of the differentiated epithelial phenotype and gain of some characteristics o f tumor cells. Our data provide novel insights into how MMPs function in development and neoplastic conversion.