Mammary ductal morphogenesis requires paracrine activation of stromal EGFR via ADAM17-dependent shedding of epithelial amphiregulin

Sternlicht, Mark D.; Sunnarborg, Susan W.; Kouros-Mehr, Hosein; Yu, Ying; Lee, Dong Hoon; Werb, Zena

doi:10.1242/dev.01966

Cited by 265 publications

(246 citation statements)

References 64 publications

(67 reference statements)

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“…Nevertheless, the under-developed EGFR-null transplants still formed alveoli in response to prolactin from adjacent pituitary isografts, suggesting that EGFR was essential for ductal but not alveolar development. Similar recombination studies were later performed in the presence of slow-release estradiol pellets in order to also assess the role of EGFR in estrogen-induced alveolar differentiation, and once again, wild-type and EGFR-null epithelium grew in fat pads that contained EGFR, but not in EGFR-null fat pads [28]. And, as was true for pituitary prolactin, EGFR was not required for estrogen-induced alveolar expansion.…”

Section: Stromal Egfr Is Required For Mammary Developmentmentioning

confidence: 90%

“…Although the above genetic evidence indicates that AREG is uniquely required for normal mammary morphogenesis [25], other studies had shown that several EGFR ligands could rescue ductal development in ovariectomized and ERα-deficient mice [26,[31][32][33] and that all EGFR ligands had comparable effects in culture [17,28]. So why were other EGFR agonists unable to compensate for the absence of AREG in vivo?…”

Section: Epithelial Areg Is Essential For Mammary Developmentmentioning

confidence: 99%

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The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

Sternlicht

Sunnarborg

2008

J Mammary Gland Biol Neoplasia

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In order to fulfill its function of producing and delivering sufficient milk to newborn mammalian offspring, the mammary gland first has to form an extensive ductal network. As in all phases of mammary development, hormonal cues elicit local intra-and inter-cellular signaling cascades that regulate ductal growth and differentiation. Among other things, ductal development requires the epidermal growth factor receptor (EGFR), its ligand amphiregulin (AREG), and the transmembrane metalloproteinase AD-AM17, which can cleave and release AREG from the cell surface so that it may interact with its receptor. Tissue recombination and transplantation studies demonstrate that EGFR phosphorylation and ductal development proceed only when ADAM17 and AREG are expressed on mammary epithelial cells and EGFR is present on stromal cells, and that local administration of soluble AREG can rescue the development of ADAM17-deficient transplants. Thus proper mammary morphogenesis requires the ADAM17-mediated release of AREG from ductal epithelial cells, the subsequent activation of EGFR on stromal cells, and EGFR-dependent stromal responses that in return elicit a new set of epithelial responses, all culminating in the formation of a fully functional ductal tree. This, however, raises new issues concerning what may act upstream, downstream or in parallel with the ADAM17-AREG-EGFR axis, how it may become hijacked or corrupted during the onset and evolution of cancer, and how such ill effects may be confronted.

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Section: Stromal Egfr Is Required For Mammary Developmentmentioning

confidence: 90%

Section: Epithelial Areg Is Essential For Mammary Developmentmentioning

confidence: 99%

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

Sternlicht

Sunnarborg

2008

J Mammary Gland Biol Neoplasia

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“…MMPs and the related families of proteinases, the ADAMs (a disintegrin and metalloproteases) and ADAM-TSs (ADAMs with thrombo spondin repeats), are important in shedding plasma-membrane-bound proteins. ADAMs and ADAM-TSs participate in shedding growth factors that are synthesized as cell-membrane-bound precursor forms, including heparin-binding epidermal growth factor (HB-EGF), neuregulin, amphiregulin and transforming growth factor-α (TGFα) [25][26][27][28] . Cleavage of other membrane proteins, such as Ecadherin and CD44, results in the release of specific, biologically active fragments of their extra cellular domains, and in increased invasive behaviour 29,30 .…”

Section: Functions Of Mmp Proteolysismentioning

confidence: 99%

“…• Epidermal-growth-factor receptor (EGFR) ligands need to be processed to function 28,[142][143][144] Cell survival…”

Section: Proliferationmentioning

confidence: 99%

Matrix metalloproteinases and the regulation of tissue remodelling

Page-McCaw

Ewald

Werb

2007

Nat Rev Mol Cell Biol

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2,585

2,180

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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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“…Second, primary mammary glands can be cultured, infected with lentiviral or retroviral expression vectors, and transplanted back into wild-type mammary glands (Welm et al, 2005). Lastly, primary mammary organoids cultured in Matrigel can develop into highly branched structures in the presence of growth factors (Sternlicht et al, 2005). The organoids can be cultured with specific inhibitors or viral vectors for analysis of mammary branching.…”

Section: Transcription Factorsmentioning

confidence: 99%

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

Kouros-Mehr¹,

Werb

2006

Developmental Dynamics

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177

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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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Mammary ductal morphogenesis requires paracrine activation of stromal EGFR via ADAM17-dependent shedding of epithelial amphiregulin

Cited by 265 publications

References 64 publications

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

Matrix metalloproteinases and the regulation of tissue remodelling

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

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