Anti-Protease Inhibition of the Progression of Precursor Lesions to Malignant Mammary Cancer in a Transgenic Animal Model
Abstract
Matrix metalloproteinases (MMPs) contribute to cancer progression. Here we show that MMP-3/stromelysin-l (Stri) can promote both tumor initiation and epithelial-to- mesenchymal conversion seen in advanced cancers. Transgenic mice that expressed Strl in mammary epithelium developed fibrosis (77%), hyperplasias (64%), dysplasias (20%) and carcinomas (7%), whereas non-transgenic controls developed only mild fibrosis and/or hyperplasias (<10%). When functionally normal cultured mammary epithelial cells were transfected with a tetracycline (Tet)-repressible Stri expression vector, Stri induction resulted in E-cadherin cleavage, scaflered growth, replacement of cytokeratins by vimentin, and acquisition of the ability to invade Matrigel and grow in soft agar. These cells, when injected into surgically cleared mammary fat pads of immunodeficient mice, formed ductal structures when Stri expression was repressed by adding Tet to the drinking water, but formed vimentin-positive, spindle-cell tumors in 30% of injected sites when Stri was induced. Large tumors grew at all sites when the cells were preinduced before injection, even with Test present. cDNA array profiling showed that Stri caused coordinated changes in the expression of intermediate filament markers and regulators of cell cycle progression, apoptosis and cell-matrix interactions. Our data suggest that, by altering the cellular microenvironment, Stri can regulate the expression of genes that control cancer development.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 1998
- Accession Number
- ADB241897
Entities
People
- Mark D. Sternlicht
Organizations
- University of California, San Francisco