An intact basement membrane (BM) is essential for the proper function, differentiation and morphology of many epithelial cells. The disruption or loss of this BM occurs during normal development as well as in the disease state. To examine the importance of BM during mammary gland development in vivo, we generated transgenic mice that inappropriately express autoactivating isoforms of the matrix metalloproteinase stromelysin-1. The mammary glands from these mice are both functionally and morphologically altered throughout development. We have now documented a dramatic incidence of breast tumors in several independent lines of these mice. These data suggest that overexpression of stromelysin-1 and disruption of the BM may be a key step in the multi-step process of breast cancer.
Keywordsproteinases; ECM; metastasis; mammary gland; branching morphogenesis Proteinases have been shown to play a role in tissue remodeling during the normal processes of embryo implantation, wound healing, ovulation, and involution of the uterus, prostate and mammary gland (for review see ref 1). Extracellular matrix (ECM)-degrading proteinases have also been implicated in pathological processes such as rheumatoid arthritis and in all stages of tumor progression, including growth, angiogenesis, invasion and metastasis (for review see ref 2). In order for tumor cells to spread to other parts of the body, they must gain entry to the stroma, where they penetrate the lymph nodes or blood vessels (intravasation) and thereby the systemic circulation. Once carried to a distant site from the primary tumor, surviving cells may exit the circulation (extravasation) into the target organ and form a secondary tumor colony (metastases). ECM-degrading proteinases have been implicated in the intra-and extravasation of tumor cells across basement membranes (BM) (for review see refs 3,4). A variety of ECM-degrading enzymes, including matrix metalloproteinases and serine proteinases, have been shown to be induced or activated in tumor cells. [4][5][6] We have recently described the production and characterization of transgenic mice that overexpress the matrix metalloproteinase stromelysin-1 (SL-1) in the mammary gland. 7 The mammary gland of prepubertal female mouse is essentially quiescent. However, with the onset of ovarian activity (between 20-25 days), primary ducts, once confined to the immediate area of the teat, form large, club-shaped terminal end buds and infiltrate the fat pad. These ducts usually arrive at the end of the fat pad at about day 70 (mature virgin), and the gland remains dormant until pregnancy. Examination of glands taken from normal 70-day virgin females revealed the typical branching pattern ( Figure 1A). However, the mammary glands from SL-1 transgenic mice, which express very low levels of the transgene, showed precocious alveolar development and maturation, with primary and NIH Public Access Figure 1C). This phenotype is both morphologically and functionally (as measured by their ability to express ( -casein) very simi...
