Site-specific inductive and inhibitory activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis

Wiseman, Bryony; Sternlicht, Mark D.; Lund, Leif R.; Alexander, Caroline M.; Mott, Joni D.; Bissell, Mina J.; Soloway, Paul D.; Itohara, Shigeyoshi; Werb, Zena

doi:10.1083/jcb.200302090

Cited by 266 publications

(299 citation statements)

References 51 publications

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“…Combined pharmacological and genetic analysis of MMP2 and MMP3 revealed a role for MMP activity during mammary development 54 . Branching morphogenesis in the mammary gland occurs by two spatially and temporally distinct mechanisms: terminal end bud (TEB) elongation and secondary branching.…”

Section: Mmp2 and Mmp3 In Mammary Developmentmentioning

confidence: 99%

“…Mmp2-and Mmp3-null mammary glands have reciprocal phenotypes in branching morphogenesis. Mmp2-null mammary glands are deficient in TEB invasion, but have an excess of secondary branches, whereas Mmp3-null mammary glands have normal invasion, but are characterized by deficient secondary branching 54 (FIG. 4b).…”

Section: Mmp2 and Mmp3 In Mammary Developmentmentioning

confidence: 99%

“…Inhibition of MMP function with a chemical inhibitor (GM6001) results in deficient primary invasion and an excess of secondary branches. Overexpression of the endogenous MMP inhibitor TIMP1 limits TEB invasion, but has a minor effect on secondary branching 54 . These observations led to a model in which MMP2 promotes ductal invasion and inhibits secondary branching, whereas MMP3 promotes secondary-branch initiation.…”

Section: Mmp2 and Mmp3 In Mammary Developmentmentioning

confidence: 99%

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Matrix metalloproteinases and the regulation of tissue remodelling

Page-McCaw

Ewald

Werb

2007

Nat Rev Mol Cell Biol

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Matrix metalloproteinases (MMPs) were discovered because of their role in amphibian metamorphosis, yet they have attracted more attention because of their roles in disease. Despite intensive scrutiny in vitro, in cell culture and in animal models, the normal physiological roles of these extracellular proteases have been elusive. Recent studies in mice and flies point to essential roles of MMPs as mediators of change and physical adaptation in tissues, whether developmentally regulated, environmentally induced or disease associated.The founding member of the matrix metalloproteinase (MMP) family, collagenase, was identified in 1962 by Gross and Lapiere, who found that tadpole tails during metamorphosis contained an enzyme that could degrade fibrillar collagen 1,2 . Subsequently, an interstitial collagenase, collagenase-1 or MMP1, was found in diseased skin and synovium 3 . In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775-Ile776 or Gly775-Lys776 in native type I, II or III collagen molecules 3,4 . Further research led to the discovery of a family of structurally related proteinases (23 in human, 24 in mice), now referred to as the MMP family.Interest in MMPs increased in the late 1960s and early 1970s following observations that MMPs are upregulated in diverse human diseases including rheumatoid arthritis and cancer. Importantly, high levels of MMPs often correlated with poor prognosis in human patients (reviewed in REF. 5 ). However, recent clinical data indicate that the relationship between § These authors contributed equally to this paper. Competing interests statementThe authors declare no competing financial interests. DATABASESThe following terms in this article are linked online to: Entrez Genome: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene DmMmp1 | DmMmp2 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMMPs and disease is not simple; for example, increased MMP activity can enhance tumour progression or can inhibit it (reviewed in REF. 6 ). This complex relationship between MMP expression and cancer has increased the basic and clinical interest in understanding MMP function in vivo, but it has also focused attention on MMPs and pathology, and relatively less attention has been focused on the normal roles of these enzymes. MMP proteolysisMMPs are members of the metzincin group of proteases, which are named after the zinc ion and the conserved Met residue at the active site 11,12 . Recent work has generated a unified peptidase nomenclature 13 Functions of MMP proteolysisHistorically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. However, MMP proteolysis can create space for cells to migrate, can produce specific substrate-cleavage fragments with independent biological activity, can MMPs in bone modelling and remodellingBone is an important site of ongoing tissue remodelling during development...

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Section: Mmp2 and Mmp3 In Mammary Developmentmentioning

confidence: 99%

Section: Mmp2 and Mmp3 In Mammary Developmentmentioning

confidence: 99%

Section: Mmp2 and Mmp3 In Mammary Developmentmentioning

confidence: 99%

See 1 more Smart Citation

Matrix metalloproteinases and the regulation of tissue remodelling

Page-McCaw

Ewald

Werb

2007

Nat Rev Mol Cell Biol

Self Cite

2,585

2,180

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“…The matrix metalloproteinases MMP-14 (MT1-MMP) and MMP-3 (stromelysin-1) are enriched in the stroma of the TEBs and mature ducts, respectively (Wiseman et al, 2003). The transcription factor Ets-5 is enriched in the TEB epithelium, whereas cytokeratins 8 and 18 are expressed throughout the epithelium of TEBs and the luminal epithelium of mature ducts (Chotteau-Lelievre et al, 2003).…”

Section: Proof-of-concept Analysismentioning

confidence: 99%

Candidate regulators of mammary branching morphogenesis identified by genome‐wide transcript analysis

Kouros-Mehr¹,

Werb

2006

Developmental Dynamics

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The mammary gland develops in a process known as branching morphogenesis, whereby a distal epithelial bud extends and bifurcates to form an extensive ductal network. Compared with other branched organs, such as the lung and kidney, little is known about the molecular basis of branching in the mammary gland. Here we report a microarray profiling strategy to identify novel genes that may regulate mammary branching. We microdissected terminal end bud (TEB) and mature duct microenvironments from ␤-actin-green fluorescent protein reporter mice and compared their RNA expression profiles with epithelium-free mammary stroma by means of microarray. We identified 1,074 genes enriched in the TEB microenvironment, 222 genes enriched in the mature duct microenvironment, and 385 genes enriched in both TEB and mature duct microenvironments. The microarray correctly predicted the expression of genes known to be enriched in the epithelium (Ets-5) and stroma (MMP-14) of TEBs and in the mature duct microenvironment (MMP-3). The microarray also correctly predicted the localization of previously uncharacterized genes, such as the TEB-enriched SPRR-1a, the duct-enriched casein-␥, and the general epithelial marker pleiotrophin. Analysis of genes enriched in TEBs revealed several genes in the Wnt (Wnt-2, Wnt-5a, Wnt-7b, Dsh-3, Frizzled-1, Frizzled-2), hedgehog (Dhh), ephrin (Ephrin-B1, Eph-A2), and transcription factor (Twist-1, Twist-2, Snail) families. In situ hybridization verified that these genes were enriched in the TEB epithelium (Wnt-5a, Wnt-7b, Dhh, Eph-A2) or TEB stroma (Wnt-2, Frizzled-1, Ephrin-B1). We discuss the potential roles of these genes in mammary branching morphogenesis. Developmental Dynamics 235:3404 -3412, 2006.

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“…Matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) are among the ECM degrading enzymes and their inhibitors critical for mammary gland morphogenesis. Deregulation of levels and/or activities of these enzymes and inhibitors were shown to result in disruption of normal breast epithelial architecture (Fata et al, 1999;Sternlicht et al, 1999;Wiseman et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

TIMP-1 regulation of cell cycle in human breast epithelial cells via stabilization of p27KIP1 protein

et al. 2006

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Increasing evidence suggests that tissue inhibitor of metalloproteinases-1 (TIMP-1) can directly regulate cell growth and apoptosis independent of its matrix metalloproteinases (MMPs)-inhibitory activity. While TIMP-1's antiapoptotic activity has been well demonstrated, conflicting data has been reported regarding TIMP-1's role in growth regulation. Here we show that TIMP-1 reduces the growth rate of human breast epithelial (MCF10A) cells by inducing cell cycle arrest at G 1 . TIMP-1-mediated cell cycle arrest is associated with its downregulation of cyclin D 1 and upregulation of p27 KIP1 , resulting in inhibition of cyclin-dependent kinase activity necessary for phosphorylation of the tumor suppressor retinoblastoma protein. We further show that TIMP-1 modulation of cyclin D 1 and p27 KIP1 is achieved through TIMP-1-mediated differential regulation of protein stability independent of growth factor signaling. We also show that TIMP-1-mediated differential regulation of cyclin D 1 and p27 KIP1 is independent of cell adhesion signaling. Whereas approximately 50% of MCF10A cells with reduced TIMP-1 expression underwent cell death following loss of cell adhesion (anoikis), TIMP-1 overexpressing cells remained viable with prominent cell cycle arrest without detectable cell death. Taken together, we propose that TIMP-1-mediated cell survival independent of cell adhesion is accompanied with cell cycle arrest in human breast epithelial cells, although cell cycle regulation may not be a prerequisite for TIMP-1 regulation of apoptosis in general.

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Site-specific inductive and inhibitory activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis

Cited by 266 publications

References 51 publications

Matrix metalloproteinases and the regulation of tissue remodelling

Matrix metalloproteinases and the regulation of tissue remodelling

Candidate regulators of mammary branching morphogenesis identified by genome‐wide transcript analysis

TIMP-1 regulation of cell cycle in human breast epithelial cells via stabilization of p27KIP1 protein

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