Transcriptional regulation of stromelysin-1 gene expression is altered during progression of mouse mammary epithelial cells from functionally normal to malignant.

The matrix metalloproteinase stromelysin-1 plays a central role during mammary gland development and tumor progression. To gain insight into the regulation of stromelysin-1 gene expression, the murine stromelysin-1 promoter was cloned and transfected into mouse mammary epithelial cells displaying various degrees of malignancy. A reconstituted basement membrane inhibited stromelysin-1 promoter activity in functionally normal cells, had little effect on moderately malignant cells and up-regulated the promoter in highly malignant cells. Spreading of normal and malignant cells was reduced by a reconstituted basement membrane, compared to a plastic substratum. Preventing spreading by maintenance of cells in suspension culture, regulated stromelysin-1 promoter activity in a manner similar to that on a reconstituted basement membrane. Conversely, increasing spreading by augmenting substratum adhesivity up-regulated stromelysin-1 promoter activity in tumor cells. In cells with reduced spreading in the presence of reconstituted basement membrane and in suspension culture, actin stress fibers were replaced by cortical actin bundles. In tumor cells, but not in functionally normal cells, treatment with phorbol diesters also resulted in accumulation of cortical actin and increased stromelysin-1 promoter activity. Consistent with an epithelial-to-mesenchymal conversion, regulation of stromelysin-1 gene expression in highly malignant cells was similar to its regulation in mammary fibroblasts. We conclude that the switch in transcriptional regulation of stromelysin-1 expression that occurs during epithelial-to-mesenchymal transition and conversion to tumorigenicity is related to altered regulation of signals from the cytoarchitecture.