Extracellular matrix remodeling as a regulator of stromal-epithelial interactions during mammary gland development, involution and carcinogenesis

An intact basement membrane is essential for the proper function, differentiation 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. Stromelysin-1 (SL-1), a member of the matrix metalloproteinase (MMP) family, was one of the first proteinases found to be associated with cancer. In this review we describe the role of MMPs in normal mammary gland involution. To examine the importance of basement membrane during development in vivo, we altered the MMP and tissue inhibitor of metalloproteinases (TIMP) balance in mammary gland. Inhibition of MMP synthesis by glucocorticoids or implants or transgenic overexpression of TIMP-1 delays matrix degradation and the involution process after weaning. The mammary glands from transgenic mice that inappropriately express autoactivating isoforms of SL-1 are both functionally and morphologically altered throughout development. Transgenic mammary glands have supernumerary branches, and show precocious development of alveoli that express β-casein expression and undergo unscheduled apoptosis during pregnancy. This is accompanied by progressive development of an altered stroma, which resembles that of a wound site or a tumor, and becomes fibrotic after postweaning involution, and by development of neoplasias. These data suggest that MMPs and disruption of the basement membrane may play key roles in branching morphogenesis of mammary gland, apoptosis, and stromal fibrosis as well as in induction and progression of breast cancer. These observations suggest that SL-1 and other MMPs may be useful targets for therapeutic intervention in cancer.