Expression of matrix metalloprotease-2-cleaved laminin-5 in breast remodeling stimulated by sex steroids

The extracellular matrix plays an important role in breast remodeling. We h ave shown that matrix metalloprotease-2 (MMP2) cleaves laminin-5 (Ln-5), a basement membrane component, generating a fragment called gamma 2x. Human b reast epithelial cells, while constitutively immobile on intact Ln-5, acqui re a motile phenotype on MMP2-cleaved Ln-5, We hypothesize that this mechan ism may underlie cell mobilization across the basement membrane during bran ching morphogenesis in breast development regulated by sex steroids. We rep ort that the expression of MMP2 and cleavage of Ln-5 correlate well with ti ssue remodeling and epithelial rearrangement of the breast both in vivo and in vitro. Thus, the Ln-5 gamma 2x fragment was detected by immunoblotting in sexually mature, pregnant, and postweaning, but not in prepubertal or la ctating mammary glands. Furthermore, cleaved Ln-5, as web as MMP2, became d etectable in remodeling glands from sexually immature rats treated with sex steroids, In. rat mammary gland explants, epithelial reorganization and lu minal cell morphological changes were induced by the addition of exogenous MMP2, in parallel to the appearance of cleaved Ln-5, Similar effects were o bserved 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 s ex steroids and that it may contribute to breast remodeling under physiolog ical and possibly pathological conditions.