Associate editor: J. Siegfried
Signaling through the epidermal growth factor receptor during the development of malignancy

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Abstract

The epidermal growth factor receptor (EGFR) is overexpressed and/or constitutively activated in a variety of human malignancies. Detection of increased expression levels of EGFR in cancer and the association between overexpression and decreased patient survival has led to the development of several therapeutic strategies to target this receptor. The results of early-phase clinical trials to date suggest that targeting EGFR alone may not be sufficient to eradicate established tumors. This limited antitumor efficacy as monotherapy has led to combining EGFR inhibitors with chemotherapy or radiation therapy for advanced disease, or incorporating EGFR inhibition to cancer prevention approaches. This review will discuss the role of EGFR signaling in carcinogenesis and the rationale for EGFR inhibition as a clinical prevention and treatment strategy.

Introduction

Transformation of fibroblasts by constitutively activated growth factor receptors, such as the epidermal growth factor receptor (EGFR), implicates EGFR signaling in carcinogenesis. The EGFR is a receptor tyrosine kinase that is overexpressed in a variety of human epithelial malignancies, including carcinomas of the lung, colon, ovary, bladder, and head and neck (Salomon, 1995). Mutated forms of EGFR have been identified in selected cancers where ligand-independent signaling contributes to tumor progression. EGFR stimulation mediates several properties that are critical for tumor formation and progression, including proliferation, cell motility, cell adhesion, invasion, cell survival, and angiogenesis. Autocrine or paracrine stimulation of signaling pathways through the EGFR mediates these tumorigenic functions, sometimes in a pathway-specific manner. This review will examine these signaling pathways and discuss their importance in carcinogenesis.

Section snippets

Physiologic role of epidermal growth factor receptor family tyrosine kinases

The EGFR is a 170-kDa plasma membrane glycoprotein containing an extracellular ligand-binding domain, a single transmembrane region, an intracellular domain with intrinsic tyrosine kinase activity, and a C-terminal tail that contains specific tyrosine containing sequences that become binding sites for SH2-containing signaling proteins upon phosphorylation. The EGFR is one of a family of 4 structurally similar receptors (ErbB family) that demonstrate homology in their kinase domains, but diverge

Metazoan conservation of the epidermal growth factor receptor

The importance of EGFR in basic biologic functions is reflected by the conservation of this growth factor receptor in many other organisms. In general, the size of the receptor as well as the extracellular/transmembrane/cytoplasmic domain structure has been maintained. The let-23 gene encodes a tyrosine kinase of the EGFR subfamily that is necessary for induction of the Caenorhabditis elegans vulva (Aroian et al., 1990). A single member of the EGFR tyrosine kinase family is present in the

The epidermal growth factor receptor signaling network

The ErbB family of receptors can undergo homo- or heterodimerization both constitutively and in response to ligands, thus resulting in tremendous signaling diversity (Fig. 1). EGFR/ErbB1 has several ligands that bind exclusively to the EGFR, including epidermal growth factor (EGF), transforming growth factor alpha (TGF-α), and amphiregulin. No ligand has yet been identified that binds to the second member of the ErbB family, ErbB2/Her2-neu. This receptor appears to be activated by

Pathological basis of epidermal growth factor receptor signaling during carcinogenesis

Overexpression of EGFR and its ligands, primarily TGF-α, has been detected in premalignant lesions, thus implicating this autocrine pathway in the early stages of tumor formation. Specifically, EGFR has been found to be up-regulated in oral dysplasias compared with levels in normal mucosa Rubin Grandis et al., 1998a, Rubin Grandis et al., 1998b, Srinivasan & Jewell, 2001, Bankfalvi et al., 2002. The mechanism of EGFR overexpression has been attributed to both transcriptional activation and gene

Signaling through mutant epidermal growth factor receptor in cancer

The most common mutation of the EGFR in human cancers appears to be a deletion of part of the extracellular domain that yields a constitutively active receptor that engages in ligand-independent signaling (Fig. 2). This mutation was originally identified in gliomas where it correlated with enhanced pathogenicity and chemotherapeutic resistance. Known as EGFRvIII, this 145-kDa mutant is expressed exclusively in cancer cells where it activates classic oncogenic signaling pathways Prigent et al.,

Conclusion

The EGFR is highly conserved in development and has been shown to regulate a variety of important functions in normal mammalian epithelial cells, including growth, survival, differentiation, and morphogenesis. A proto-oncogene, EGFR can induce transformation and is overexpressed in a broad array of malignancies. Although gene amplification has been reported in cancer cell lines, epigenetic causes appear to account for most cases of overexpression. Increased levels of EGFR and overproduction of

Acknowledgements

This work was supported by NIH grant CA77308 (to J.R.G.).

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