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

  • Mark D. Sternlicht
  • Susan W. Sunnarborg
Article

Abstract

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 ADAM17, 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.

Keywords

Mammary gland Branching morphogenesis Metalloproteinase ADAMs TNFα converting enzyme ErbB Stromal–epithelial interactions Epidermal growth factor receptor 

Abbreviations

ADAM

a disintegrin and metalloproteinase

AREG

amphiregulin

BTC

betacellulin

EGF

epidermal growth factor

EGFR

epidermal growth factor receptor

ENMPRIN

extracellular matrix metalloproteinase inducer

ER

estrogen receptor

ERK

extracellular signal-regulated kinase

FGF

fibroblast growth factor

FGFR

fibroblast growth factor receptor

GH

growth hormone

GPCR

G-protein coupled receptor

HB-EGF

heparin-binding EGF-like growth factor

IGF

insulin-like growth factor

MAPK

mitogen-activated protein kinase

MMP

matrix metalloproteinase

NRG

neuregulin

P13

phosphoinositide 3

PR

progesterone receptor

TACE

tumor necrosis factor alpha converting enzyme

TEB

terminal end bud

TGF

transforming growth factor

TIMP

tissue inhibitor of metalloproteinases

Notes

Acknowledgements

We thank Drs. Zena Werb and David Lee for their guidance and support. This work was supported by grants from the National Cancer Institute (CA57621, CA58207, CA43793, CA61896 and CA85410) and by a grant jointly funded by the National Institute of Environmental Health Sciences and National Cancer Institute (ES012801).

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© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.FibroGen, Inc.South San FranciscoUSA
  2. 2.Department of Biochemistry and BiophysicsUniversity of North CarolinaChapel HillUSA

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