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(American Journal of Pathology. 1999;154:1193-1201.)
© 1999 American Society for Investigative Pathology

Regular Articles

Expression of Matrix Metalloprotease-2-Cleaved Laminin-5 in Breast Remodeling Stimulated by Sex Steroids

Gianluigi Giannelli* , Ambra Pozzi* , William G. Stetler-Stevenson , Humphrey A. Gardner* and Vito Quaranta*

From the Department of Cell Biology,* The Scripps Research Institute, La Jolla, California, Institute of Clinica Medica II, Universitaí degli Studi di Bari, Bari, Italy, and Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

The extracellular matrix plays an important role in breast remodeling. We have shown that matrix metalloprotease-2 (MMP2) cleaves laminin-5 (Ln-5), a basement membrane component, generating a fragment called 2x. Human breast epithelial cells, while constitutively immobile on intact Ln-5, acquire a motile phenotype on MMP2-cleaved Ln-5. We hypothesize that this mechanism may underlie cell mobilization across the basement membrane during branching morphogenesis in breast development regulated by sex steroids. We report that the expression of MMP2 and cleavage of Ln-5 correlate well with tissue remodeling and epithelial rearrangement of the breast both in vivo and in vitro. Thus, the Ln-5 2x fragment was detected by immunoblotting in sexually mature, pregnant, and postweaning, but not in prepubertal or lactating mammary glands. Furthermore, cleaved Ln-5, as well as MMP2, became detectable in remodeling glands from sexually immature rats treated with sex steroids. In rat mammary gland explants, epithelial reorganization and luminal cell morphological changes were induced by the addition of exogenous MMP2, in parallel to the appearance of cleaved Ln-5. Similar effects were observed in epithelial monolayers plated on human Ln-5 and exposed to MMP2. These results suggest that cleavage of Ln-5 by MMP2 might be regulated by sex steroids and that it may contribute to breast remodeling under physiological and possibly pathological conditions.

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