Abstract |
Tissue remodeling is a key process involved in normal mammary gland development, with matrix metalloproteinases ( MMPs) playing an important role in this process. Our laboratory has demonstrated that tumor necrosis factor (TNF) stimulates branching morphogenesis of mammary epithelial cells (MEC) within a reconstituted basement membrane. Studies were therefore undertaken to determine whether MMPs might mediate the effects of TNF. Using a primary culture model in which rat MEC grow three-dimensionally within a reconstituted basement membrane, we found that TNF stimulated secretion of MMP-9 but not MMP-2. To determine whether MMP-9 was involved in TNF-induced proliferation and branching morphogenesis, we used a peptide containing the prodomain sequence of MMPs and two MMP inhibitors. Both the prodomain peptide (5 x 10(-4)-10(-3) M), as well as BB-94 (10(-8)-10(-5) M) and CGS 27023A (10(-6)-10(-5) M), inhibited TNF-induced proliferation and branching morphogenesis in a concentration-dependent manner. Finally, to verify the specific requirement for MMP-9, we demonstrated that an MMP-9 neutralizing antibody blocked TNF-induced proliferation and branching morphogenesis. Together, these data suggest that TNF-regulated MMP-9 may play a role in the controlled invasion of the fad pad that occurs during normal mammary gland development and that misregulation of MMP-9 may contribute to the invasiveness of breast cancer.
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Authors | P P Lee, J J Hwang, G Murphy, M M Ip |
Journal | Endocrinology
(Endocrinology)
Vol. 141
Issue 10
Pg. 3764-73
(Oct 2000)
ISSN: 0013-7227 [Print] United States |
PMID | 11014232
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Antibodies
- CGS 27023A
- Hydroxamic Acids
- Protease Inhibitors
- Pyrazines
- Sulfonamides
- Thiophenes
- Tumor Necrosis Factor-alpha
- Phenylalanine
- batimastat
- Matrix Metalloproteinase 9
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Topics |
- Animals
- Antibodies
(pharmacology)
- Cell Division
(physiology)
- Cells, Cultured
- Enzyme Induction
- Epithelial Cells
(cytology)
- Female
- Hydroxamic Acids
- Mammary Glands, Animal
(cytology)
- Matrix Metalloproteinase 9
(immunology, metabolism, physiology)
- Phenylalanine
(analogs & derivatives, pharmacology)
- Protease Inhibitors
(pharmacology)
- Pyrazines
- Rats
- Rats, Sprague-Dawley
- Sulfonamides
- Thiophenes
(pharmacology)
- Tumor Necrosis Factor-alpha
(pharmacology, physiology)
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