Site-specific inductive and inhibitory activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis |
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Authors: | Wiseman Bryony S Sternlicht Mark D Lund Leif R Alexander Caroline M Mott Joni Bissell Mina J Soloway Paul Itohara Shigeyoshi Werb Zena |
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Institution: | Department of Anatomy, University of California, San Francisco, CA 94143-0452, USA. |
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Abstract: | During puberty, mouse mammary epithelial ducts invade the stromal mammary fat pad in a wave of branching morphogenesis to form a complex ductal tree. Using pharmacologic and genetic approaches, we find that mammary gland branching morphogenesis requires transient matrix metalloproteinase (MMP) activity for invasion and branch point selection. MMP-2, but not MMP-9, facilitates terminal end bud invasion by inhibiting epithelial cell apoptosis at the start of puberty. Unexpectedly, MMP-2 also represses precocious lateral branching during mid-puberty. In contrast, MMP-3 induces secondary and tertiary lateral branching of ducts during mid-puberty and early pregnancy. Nevertheless, the mammary gland is able to develop lactational competence in MMP mutant mice. Thus, specific MMPs refine the mammary branching pattern by distinct mechanisms during mammary gland branching morphogenesis. |
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Keywords: | apoptosis matrix metalloproteinases stromal–epithelial interaction terminal end bud tissue inhibitor of metalloproteinases |
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