Abstract
Matrix metalloproteinases (MMPs) are invariably upregulated in the stromal compartment of epithelial cancers and appear to promote invasion and metastasis. Here we report that phenotypically normal mammary epithelial cells with tetracycline-regulated expression of MMP3/stromelysin-1 (Str1) form epithelial glandular structures in vivo without Str1 but form invasive mesenchymal-like tumors with Str1. Once initiated, the tumors become independent of continued Str1 expression. Str1 also promotes spontaneous premalignant changes and malignant conversion in mammary glands of transgenic mice. These changes are blocked by coexpression of a TIMP1 transgene. The premalignant and malignant lesions have stereotyped genomic changes unlike those seen in other murine mammary cancer models. These data indicate that Str1 influences tumor initiation and alters neoplastic risk.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Carcinogenicity Tests
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Cell Differentiation / drug effects
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Cell Differentiation / physiology
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Cells, Cultured
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Epithelial Cells / chemistry
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Epithelial Cells / cytology
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Epithelial Cells / metabolism
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Female
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Fibrosis
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Gene Expression Regulation, Enzymologic
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Gene Expression Regulation, Neoplastic
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Genome
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Humans
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Hyperplasia
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Keratins / analysis
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Mammary Neoplasms, Experimental / metabolism*
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Mammary Neoplasms, Experimental / pathology
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Matrix Metalloproteinase 3 / genetics
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Matrix Metalloproteinase 3 / metabolism*
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Mesoderm / cytology
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Mice
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Mice, SCID
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Mice, Transgenic
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Pregnancy
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Stromal Cells / cytology
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Stromal Cells / enzymology
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Tissue Inhibitor of Metalloproteinase-1 / pharmacology
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Vimentin / analysis
Substances
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Antineoplastic Agents
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Tissue Inhibitor of Metalloproteinase-1
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Vimentin
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Keratins
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Matrix Metalloproteinase 3