Urokinase-type plasminogen activator expression is induced in the mouse mammary gland during development

The mammary gland undergoes extensive, but finely controlled tissue remodeling throughout its growth and development. During post-pubertal maturation of the ductal tree, a variety of proteinases, growth factors and integrins are expressed in a well-regulated spatial and temporal pattern (Ossowski et al., 1979; Busso et al., 1989; Robinson et al., 1991; ColemanKmacik and Rosen, 1994; Witty et al., 1995; Faraldo et al., 1998; Thomasset et al., 1998). Synthesis of most proteinases ceases during late pregnancy and lactation. After weaning, the mammary gland is again remodeled in preparation for the next pregnancy through a complex and well-regulated cellular program. This process of involution involves the collapse of alveolar structures, removal of secretory epithelial cells by programmed cell death, phagocytosis by macrophages, proteolytic degradation of basement membranes, and stromal remodeling. Consequently, most of the differentiated epithelial cells disappear and an adipocyte-rich stroma, in which the resting ductal system is embedded, reappears (Lascelles and Lee, 1978; Walker et al., 1989; Strange et al., 1992; Talhouk et al., 1992; Marti et al., 1994; Lund et al., 1996). After 10-15 days, the structure of involuting glands approaches that of resting virgin glands (Lascelles and Lee, 1978). Based on these changes, post-lactational involution can be divided into two distinct phases. The initial phase is characterized by programmed cell death of the differentiated epithelial cells and induced expression of Bax, p53 and clusterin (Lund et al., 1996; Li et al., 1997; Jerry et al., 1998). This is followed by a second phase with extensive tissue remodeling and a characteristic spatial and temporal expression pattern of a number of extracellular proteinases (Lund et al., 1996). These include the matrix metalloproteinases (MMPs) stromelysin-1 (Str1), stromelysin3 (Str3) and gelatinase A, the serine proteinases urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA), and the cysteine proteinase cathepsin B (Ossowski et al., 1979; Busso et al., 1989; Dickson and Warburton, 1992; Lefebvre et al., 1992; Strange et al., 1992; Talhouk et al., 1992; Guenette et al., 1994; Li et al., 1994; Lund et al., 1996). The spatial distribution of mRNAs for Str1, Str3, gelatinase A and uPA in fibroblast-like cells during involution (Lefebvre et al., 1992; Lund et al., 1996) points to an active role for the mesenchymal stroma during tissue remodeling. 4481 Development 127, 4481-4492 (2000) Printed in Great Britain © The Company of Biologists Limited 2000 DEV3173