Abstract
Epidermal growth factor receptor (EGFR) comprises a dominant signalling pathway for many tumours. In breast cancer, increased expression of EGFR or its EGF-like ligands and hyperactivation of subsequent mitogen-activated protein kinase (MAPK) and protein kinase B (AKT) signalling have been linked to anti-hormone resistant growth, metastatic progression and poor prognosis. Considerable data exist detailing EGFR activation and the downstream signalling that is triggered subsequent to EGFR ligand binding, allowing rationale design of several anti-EGFR agents that are currently in clinical trials in cancers including the breast. However, less is known about the mechanisms regulating EGF-like ligand availability and their potential as therapeutic targets. EGFR ligands, including transforming growth factor α (TGFα), heparin-binding EGF (HB-EGF) and amphiregulin (AR), are expressed as transmembrane precursors. These are released from the cell surface following shedding of the extracellular domain (ectodomain shedding) by zinc-dependent proteinases. The soluble ligand can bind and activate EGFR in an autocrine or paracrine manner, while the transmembrane (pro) form may activate EGFR in adjacent cells (juxtacrine). Of emerging importance as regulators of EGFR ligand shedding is the ADAM (a disintegrin and metalloprotease) family of membrane glycoproteins. This family currently comprises 34 members. However, the nature of individual ADAMs required for EGFR ligand shedding, and their role in EGFR activation and its interaction with other signalling pathways, remain poorly defined in tumour cells. Three new articles examining ADAM17 (TNFα-converting enzyme; TACE) and ADAM10 (Kuzbanian) shed light in these areas. Borrell-Pages et al. [1] establish relevance of TACE to TGFα shedding and EGFR signalling in clinical breast cancer, while Gschwind et al. [2] and Yan et al. [3] reveal that TACE and ADAM10 contribute to the interplay between EGFR and diverse signalling pathways.
Highlights
Epidermal growth factor receptor (EGFR) comprises a dominant signalling pathway for many tumours
The nature of individual ADAMs required for EGFR ligand shedding, and their role in EGFR activation and its interaction with other signalling pathways, remain poorly defined in tumour cells
The recent articles by Borrell-Pages et al, Yan et al, and Gschwind et al demonstrate that ADAMs are important regulators of EGFR ligand shedding and EGFR activation in tumour cells, contributing to the productive “cross-talk” between diverse signalling pathways and EGFR
Summary
Epidermal growth factor receptor (EGFR) comprises a dominant signalling pathway for many tumours. ADAM = a disintegrin and metalloprotease; AKT = protein kinase B; AR = amphiregulin; EGF = epidermal growth factor; EGFR = epidermal growth factor receptor; GPCR = G protein coupled receptor; HB-EGF = heparin-binding epidermal growth factor; IGFR = insulin-like growth factor receptor; MAPK = mitogen-activated protein kinase; MMP = matrix metallo protease; TACE = tumour necrosis factor α-converting enzyme; TGFα =. IGFR-EGFR cross-talk is certainly apparent in mammary epithelial cells, since EGFR blockade abrogates IGFR-driven MAP kinase signalling and primes apoptosis It remains controversial whether this cross-talk involves metalloprotease-mediated EGFR ligand release [7] and studies investigating IGFREGFR interactions are ongoing in breast cancer. While the matrix metalloproteases MMP2 and MMP9 appear to play a role in GPCR-mediated HB-EGF release, the full profile of metalloproteases, including ADAMs, contributing to EGFR transactivation and its end-points remains to be defined in breast cancer
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