Epidermal growth factor receptor (EGFR) signaling in cancer (original) (raw)
Related papers
An Open-and-Shut Case? Recent Insights into the Activation of EGF/ErbB Receptors
Molecular Cell, 2003
Since its discovery more than 40 years ago (Cohen, P.O. Box 2008 1960), epidermal growth factor (EGF) has provided nu-Royal Melbourne Hospital merous puzzles for biologists, biochemists, physicists, 3 Walter and Eliza Hall Institute of Medical Research and oncologists (Jorissen et al., 2003; Schlessinger, 1G Royal Parade 2002). In the past year, major advances in understanding Parkville, Victoria 3050 EGF action have come from crystallographic studies of 4 CSIRO Health Science and Nutrition extracellular regions from three members of the EGF 343 Royal Parade receptor (EGFR) or ErbB family: namely EGFR itself, Parkville, Victoria 3052 ErbB2 (HER2/Neu), and ErbB3 (HER3) (see Table 1). The Australia structures have yielded several surprises. A dramatic 5 Department of Biology conformational transition was shown to occur upon li-Yonsei University gand binding; an unprecedented (entirely receptor-Shinchon-dong 134 mediated) mode of dimerization was identified; and an Seodaemun-gu, Seoul 120-749 unexpected apparently "preactivated" state was de-Korea fined for the ErbB2 monomer. By combining the informa-6 Department of Biophysics and Biophysical Chemistry tion gained from the recent structural studies, we have Howard Hughes Medical Institute been able to develop models for the allosteric regulation The Johns Hopkins University School of Medicine of EGFR family members. These models have greatly Baltimore, Maryland 21205 improved our understanding of ErbB receptor signaling 7 Department of Protein Engineering and have created opportunities for the design of new 8 Department of Molecular Oncology anticancer agents. Genentech Inc. EGFR was the first cell-surface receptor to be linked South San Francisco, California 94080 directly to cancer when Stanley Cohen and colleagues 9 Department of Physiology described the downregulation of EGFR in fibroblasts 10 ). The findings that EGFR is a ligand-dependent Philadelphia, Pennsylvania 19104 tyrosine kinase (Ushiro and Cohen, 1980) and that the 11
Cytometry
Background: Receptors belonging to the epidermal growth factor receptor (EGFR) family transfer extracellular signals by homotypic and heterotypic receptor interaction and cross-activation. Cell differentiation, death, and proliferation are regulated via these receptor-tyrosine-kinases. However, the initial mechanisms that lead to signal specificity and diversity, which cause a defined cellular response, are incompletely understood. We investigated the recruitment of receptor complexes in two c-erbB2overexpressing breast carcinoma cell lines, SK-BR-3 and BT474, after ligand binding and its effects on intracellular signal transduction and cell cycle regulation. Methods: In order to analyze the coaggregation of receptors on the cell surface induced by specific growth factor treatment, we used the flow cytometric Foerster-type fluorescence resonance energy transfer (FRET) technique. Cell cycle kinetics were monitored flow cytometrically via the anti-BrdU technique and acitivation of intracellular signal cascades was analyzed by Western blotting. Results: After stimulation with EGF BT474, but not SK-BR-3, cells formed EGFR/c-erbB2 receptor complexes. Neither EGF nor heregulin (HRG) induced c-erbB2/c-erbB3 receptor complexes in BT474. However, SK-BR-3 cells exhibited a high amount of c-erbB2/c-erbB3 heterodimers even without growth factor stimulation which could be elevated after prolonged EGF and HRG treat-ment. In both cell lines, mitogen-activated protein kinase (MAPK) phosphorylation was detectable after short-term and prolonged EGF and HRG treatment. However, only SK-BR-3 cells showed a constitutive activation of both protein kinase B (PKB)/Akt and MAPK signaling pathways. Growth factor treatment caused an amplified PKB/Akt activation in this cell line. The induction of EGFR/c-erbB2 complexes in BT474 was associated with shortening of the G1-phase of the cell cycle. In contrast, the concurrent activation of MAPK and PKB/Akt by EGF treatment led to an inhibition of proliferation in SK-BR-3 and can be attributed to missing EGFR/c-erbB2 heterodimers. HRG was a strong stimulator of proliferation in both cell lines. Conclusions: We show that in the presence of identical amounts of c-erbB2 receptors, the ligand-induced cellular response differs significantly. These differences were mediated by variances in signal transduction, most likely due to different recruitment of heterotypic receptor complexes. Overall, there is strong evidence that c-erbB2 receptor overexpression in breast cancer cells is an insufficient marker to determine cellular response in terms of cell proliferation.
Oncogenesis, 2012
Increasing the efficacy of targeted cancer therapies requires the identification of robust biomarkers suitable for patient stratification. This study focused on the identification of molecular mechanisms causing resistance against the anti-ERBB2-directed therapeutic antibodies trastuzumab and pertuzumab presently used to treat patients with ERBB2-amplified breast cancer. Immunohistochemistry and clinical data were evaluated and yielded evidence for the existence of ERBB2-amplified breast cancer with high-level epidermal growth-factor receptor (EGFR) expression as a separate tumor entity. Because the proto-oncogene EGFR tightly interacts with ERBB2 on the protein level, the hypothesis that high-level EGFR expression might contribute to resistance against ERBB2-directed therapies was experimentally validated. SKBR3 and HCC1954 cells were chosen as model systems of EGFRhigh/ERBB2-amplified breast cancer and exposed to trastuzumab, pertuzumab and erlotinib, respectively, and in combination. Drug impact was quantified in cell viability assays and on the proteomic level using reverse-phase protein arrays. Phosphoprotein dynamics revealed a significant downregulation of AKT signaling after exposure to trastuzumab, pertuzumab or a coapplication of both antibodies in SKBR3 cells but no concomitant impact on ERK1/2, RB or RPS6 phosphorylation. On the other hand, signaling was fully downregulated in SKBR3 cells after coinhibition of EGFR and ERBB2. Inhibitory effects in HCC1954 cells were driven by erlotinib alone, and a significant upregulation of RPS6 and RB phosphorylation was observed after coincubation with pertuzumab and trastuzumab. In summary, proteomic data suggest that high-level expression of EGFR in ERBB2-amplified breast cancer cells attenuates the effect of anti-ERBB2-directed antibodies. In conclusion, EGFR expression may serve as diagnostic and predictive biomarker to advance personalized treatment concepts of patients with ERBB2-amplified breast cancer.
Brit J Cancer, 2004
The epidermal growth factor receptor (EGFR) family plays an important role in breast carcinogenesis. Much interest has been focused recently on its members because of their potential role as prognostic indicators in breast cancer and their involvement in cancer therapy. We have evaluated more than 1500 cases of invasive breast carcinoma immunohistochemically using tissue microarray technology to examine the expression of EGFR family receptor proteins. We have found that 20.1 and 31.8% of cases were positive for EGFR and c-erbB-2, respectively, and 45 and 45.1% of tumours overexpressed for c-erbB-3 and c-erbB-4, respectively. The expression of either EGFR or c-erbB-2 was associated with other bad prognostic features and with poor outcome. Neither c-erbB-3 nor c-erbB-4 had any association with survival. c-erbB-2 had an independent prognostic effect on overall and disease-free survival (DFS) in all cases, as well as in the subset of breast carcinoma patients with nodal metastases. Several hetero-and homodimeric combinations have been reported between the EGFR members. Those dimers can evoke diverse signal transduction pathways with variable cellular responses. We stratified cases according to their co-expression of receptors into distinct groups with different receptor-positive combinations. Patients whose tumours co-expressed c-erbB-2 and c-erbB-3, as well as those whose tumours coexpressed EGFR, c-erbB-2 and c-erbB-4 showed an unfavourable outcome compared with other groups, while combined c-erbB-3 and c-erbB-4 expression was associated with a better outcome. In cases showing expression of one family member only (homodimers), we found a significant association between c-erbB-4 homodimer-expressing tumours and better DFS. In contrast, patients with c-erbB-2 homodimer-expressing tumours had a significant poorer DFS compared with other cases. These data imply that the combined profile expression patterns of the four receptor family members together provide more accurate information on the tumour behaviour than studying the expression of each receptor individually.
Journal of Mammary Gland Biology and Neoplasia, 1997
The ErbB/HER family of transmembrane receptor tyrosine kinases includes four members that bind more than two dozens ligands sharing an epidermal growth factor- (EGF)3 like motif. This family plays a pivotal role in cell lineage determination in a variety of tissues, including mesenchyme-epithelial inductive processes and the interactions between neurons and muscle, glia and Schwann cells. Certain ligands and receptors of the family, especially the ErbB-2 receptor tyrosine kinase, contribute to a relatively virulent phenotype of some human tumors; most notable are carcinomas of secretory epithelia. This large variety of biological signals is generated through a combinatorial network of signal transduction in which different ErbB ligands are apparently capable of stabilizing discrete homo- and heterodimeric receptor complexes, each coupled to a specific set of cytoplasmic signaling proteins. Because each receptor is unique in terms of catalytic activity, cellular routing and transmodulation, the resulting network allows not only an enormous potential for signal diversification but also fine tuning and stringent control of cellular functions. ErbB-2 emerges as a master coordinator of the network, prolonging and amplifying signaling by decelerating the dissociation rates of its heterologous ligands. Thus, the tumorigenic action of ErbB-2 may be attributed to its ability to act as a shared signaling subunit, rather than by functioning as a bone fide receptor.
The complexity of targeting EGFR signalling in cancer: From expression to turnover
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2006
The epidermal growth factor receptor (ErbB1 or EGFR) has been found to be altered in a variety of human cancers. A number of agents targeting these receptors, including specific antibodies directed against the ligand-binding domain of the receptor and small molecules that inhibit kinase activity are either in clinical trials or are already approved for clinical treatment. However, identifying patients that are likely to respond to such treatments has been challenging. As a consequence, it still remains important to identify additional alterations of the tumor cell that contribute to the response to EGFR-targeted agents. While EGFR-mediated signalling pathways have been well established, there is still a rather limited understanding of how intracellular protein-protein interactions, ubiquitination, endocytosis and subsequent degradation of EGFR contribute to the determination of sensitivity to EGFR targeting agents and are emerging areas of investigation. This review primarily focuses on the basic signal transduction pathways mediated through activated membrane bound and/or endosomal EGFR and emphasizes the need to co-target additional proteins that function either upstream or downstream of EGFR to improve cancer therapy.
Rational bases for the development of EGFR inhibitors for cancer treatment
The International Journal of Biochemistry & Cell Biology, 2007
Growth factor receptors and their ligands not only regulate normal cell processes but have been also identified as key regulators of human cancer formation. The epidermal growth factor receptor (EGFR/ErbB1/HER1) belongs to the ErbB/HER-family of tyrosine kinase receptors (RTKs). These trans-membrane proteins are activated following binding with peptide growth factors of the EGFfamily of proteins. Several evidences suggest that cooperation of multiple ErbB receptors and ligands is required for the induction of cell transformation. In this respect, EGFR, upon activation, sustains a complex and redundant network of signal transduction pathways with the contribution of other trans-membrane receptors. EGFR has been found to be expressed and altered in a variety of malignancies and clearly it plays a significant role in tumor development and progression, including cell proliferation, regulation of apoptotic cell death, angiogenesis and metastatic spread. Moreover, amplification of the EGFR gene and mutations in the EGFR tyrosine kinase domain have been recently reported in human carcinomas. As a result, investigators have developed approaches to inhibit the effects of EGFR activation, with the aim of blocking tumor growth and invasion. A number of agents targeting EGFR, including specific antibodies directed against its ligand-binding domain and small molecules inhibiting its tyrosine kinase activity are either in clinical trials or are already approved for clinical treatment.
The EMBO Journal, 1988
The epidermal growth factor receptor (EGF-R) and the erbB-2 proto-oncogene product protein are closely related by their structural homology and their shared enzymatic activity as autophosphorylating tyrosine kinases. We show that in mammary tumor cells (SK-BR-3) EGF causes a rapid increase in tyrosine phosphorylation of the erbB-2 protein. Phosphorylation of erbB-2 does not occur in cells lacking the EGF-R (IMA-M1B453). Phosphorylation of erbB-2 in SK-BR-3 cells is blocked if EGF is prevented from interacting with its receptor by specific monoclonal antibodies. While EGF induces the downregulation of its receptor in SK-BR-3 cells, EGF has no effect on the stability of the erbB-2 protein. This result suggests that the erbB-2 protein is a substrate of the EGF-R and indicates the possibility of communication between these two proteins early in the signal transduction process.