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

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.

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Figure 1

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

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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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Correspondence to Mark D. Sternlicht.

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Sternlicht, M.D., Sunnarborg, S.W. The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer. J Mammary Gland Biol Neoplasia 13, 181–194 (2008). https://doi.org/10.1007/s10911-008-9084-6

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Keywords

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