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 Page: 2 of 28
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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.
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Lochter, A.; Galosy, S.; Muschler, J.; Freedman, N.; Werb, Z. & Bissell, M.J. 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, article, August 11, 1997; Berkeley, California. (digital.library.unt.edu/ark:/67531/metadc829363/m1/2/: accessed January 21, 2019), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT Libraries Government Documents Department.