Regulation of functional cytodifferentiation and histogenesis in mammary epithelial cells: role of the extracellular matrix.

Primary mammary epithelial cells provide a versatile system for the study of hormone and extracellular matrix (ECM) influences on tissue-specific gene expression. We have characterized the formation of alveolarlike morphogenesis and mammary-specific functional differentiation that occur when these cells are cultured on a reconstituted basement membrane (EHS). Cells cultured on EHS exhibit many ultrastructural and biochemical features indicative of polarized and functionally differentiated mammary epithelium in vivo. The increased expression and specific vectorial secretion of milk proteins into lumina formed in culture are accompanied by large increases in milk protein mRNA expression. However, when individual ECM components are tested, smaller increases in milk protein mRNA are measured on heparan sulfate proteoglycan (HSPG) and laminin, and these responses are not associated with full functional cytodifferentiation or histotypic configuration. This indicates that multiple levels of regulation are involved in mammary-specific gene expression, and that in addition to individual ligand requirements cooperative interactions between various ECM molecules and cells are necessary for functional differentiation in culture. We have also shown that endogenous production of ECM molecules and changes in cell geometry are correlated with changes in functional and histogenic gene expression. We have previously proposed a model of cell-ECM interactions that is consistent with these data.