Expression of c-ets-1 and uPA genes is associated with mammary epithelial cell tubulogenesis or neoplastic scattering

Although the inductive interactions which trigger epithelial morphogenesis have been extensively described, little is known about the transcription factors involved in these processes. During mammary gland morphogenesis, we report the expression of the transcription factor c-ets-1 and one of its target genes uPA in mesenchymal cells during early stages of epithelial invasion, and later in epithelial cells themselves. In vitro studies show that both c-ets-1 and uPA mRNAs can be induced in cultured normal mammary epithelial cells in response to medium conditioned by MRC-5 fibroblasts. In contrast, invasive tumorigenic cell lines from the mammary epithelium express constitutively c-ets-1 and uPA while non-invasive tumorigenic cells do not. In three dimensional co-cultures in collagen gels, a preferential expression of these genes is detected in epithelial cells migrating through the gel either at the tips of normal ducts or in cancerous cells which are scattering. These genes are also expressed in the neighboring fibroblasts. In MRC-5 fibroblasts, conditioned media from tumorigenic epithelial cells induce more efficiently c-ets-1 and uPA mRNA accumulation than do conditioned medium from normal cells. These results suggest that epithelial-mesenchymal interactions trigger c-ets-1 and uPA expression in both compartments during mammary gland morphogenesis. The expression of the genes correlates with invasiveness of epithelial cells irrespective of their being normal or cancerous.