The interplay of matrix metalloproteinases, morphogens and growth factors is necessary for branching of mammary epithelial cells

Journal Article · Wed Mar 06 04:00:00 EST 2002 · Development

OSTI ID:793736

Simian, Marina ^[1]; Hirai, Yohei; Navre, Marc; Werb, Zena; Lochter, Andre; Bissell, Mina J

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1. LBNL Library

The mammary gland develops its adult form by a process referred to as branching morphogenesis. Many factors have been reported to affect this process. We have used cultured primary mammary epithelial organoids and mammary epithelial cell lines in three-dimensional collagen gels to elucidate which growth factors, matrix metalloproteinases (MMPs) and mammary morphogens interact in branching morphogenesis. Branching stimulated by stromal fibroblasts, epidermal growth factor, fibroblast growth factor 7, fibroblast growth factor 2 and hepatocyte growth factor was strongly reduced by inhibitors of MMPs, indicating the requirement of MMPs for three-dimensional growth involved in morphogenesis. Recombinant stromelysin 1/MMP-3 alone was sufficient to drive branching in the absence of growth factors in the organoids. Plasmin also stimulated branching; however, plasmin-dependent branching was abolished by both inhibitors of plasmin and MMPs, suggesting that plasmin activates MMPs. To differentiate between signals for proliferation and morphogenesis, we used a cloned mammary epithelial cell line that lacks epimorphin, an essential mammary morphogen. Both epimorphin and MMPs were required for morphogenesis, but neither was required for epithelial cell proliferation. These results provide direct evidence for a critical role of MMPs in branching in mammary epithelium and suggest that, in addition to epimorphin, MMP activity is a minimum requirement for branching morphogenesis in the mammary gland.

• Research Organization: Ernest Orlando Lawrence Berkeley National Lab., CA (US)
• Sponsoring Organization: Human Frontiers Science Program RG0051/1999M; Science and Technology Agency of Japan (US)
• DOE Contract Number: AC03-76SF00098
• OSTI ID: 793736
• Report Number(s): LBNL--44575
• Journal Information: Development, Journal Name: Development Journal Issue: 16 Vol. 128
• Country of Publication: United States
• Language: English

Related Subjects

98 NUCLEAR DISARMAMENT, SAFEGUARDS, AND PHYSICAL PROTECTION
BRANCHING MORPHOGENESIS MAMMARY GLAND STROMELYSIS 1 EPIMORPHIN PLASMINOGEN STROMAL/EPITHELIAL INTERACTIOSN MOUSE
CELL PROLIFERATION
COLLAGEN
EPITHELIUM
FIBRINOLYSIN
FIBROBLASTS
GOLGI COMPLEXES
GROWTH FACTORS
LIVER CELLS
MAMMARY GLANDS
MORPHOGENESIS
PROLIFERATION