Dynamic reciprocity: how do extracellular matrix and hormones direct gene expression?

Using mouse mammary epithelial cells (MME) as a model, we show that extracellular matrix (ECM) plays a fundamental role in the maintenance of tissue-specific function in culture. The ECM affects both the level of mRNA and the rates of synthesis and secretion of milk proteins. Casein gene expression by primary mammary epithelial cells and cell strains is controlled by both ECM and lactogenic hormones (insulin, hydrocortisone and prolactin). In the case of transferrin, the major iron-binding protein of mouse milk, the ECM rather than prolactin, appears to modulate the level of its mRNA. We further show that both ECM and lactogenic hormones influence cell shape and polarity of mammary epithelial cells. The data are consistent with a model of "Dynamic Reciprocity" (Bissell et al. 1982) where the ECM is postulated to exert an influence on gene expression via transmembrane proteins and cytoskeletal components. Cytoskeleton, in turn, is associated with polyribosomes, affecting mRNA stability and rates of protein synthesis, and with the nuclear matrix, affecting mRNA processing and, possibly, rates of transcription. We postulate that hormones and ECM act synergistically to complete the 'reciprocity' loop.