EXTRACELLULAR-MATRIX REMODELING AND THE REGULATION OF EPITHELIAL-STROMAL INTERACTIONS DURING DIFFERENTIATION AND INVOLUTION

An intact basement membrane is essential for the proper function, diff erentiation and morphology of many epithelial cells. The disruption or remodeling of the basement membrane occurs during normal development as well as in the disease state. To examine the importance of basement membrane during development in vivo, we altered the matrix metallopro teinase and tissue inhibitor of metalloproteinases balance in mammary gland. Inhibition of matrix metalloproteinase synthesis by glucocortic oids or implants or transgenic overexpression of tissue inhibitor of m etalloproteinases-1 delays matrix degradation and the involution proce ss after weaning. The mammary glands from transgenic mice that inappro priately express autoactivating isoforms of stromelysin-1 are both fun ctionally and morphologically altered throughout development. Transgen ic mammary glands have supernumerary branches, and show precocious dev elopment of alveoli that express beta-casein expression and undergo un scheduled apoptosis during pregnancy. This is accompanied by progressi ve development of an altered stroma, which becomes fibrotic after post weaning involution, and by development of neoplasias. These data sugge st that metalloproteinases and disruption of the basement membrane may play key roles in branching morphogenesis of mammary gland, cell cycl e, apoptosis, and stromal fibrosis as well as in induction and progres sion of breast cancer.