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Reviews > Proteins > Membrane Proteins > Plasma Membrane Proteins > Receptors > Epidermal Growth Factor Receptor > Epidermal Growth Factor Receptor Interactions
Epidermal Growth Factor Receptor Interactions
Published by Anonymous on 2007/9/29 (2239 reads)
1: Clin Lung Cancer. 2006 Jan;7(4):250-6.

Interactions between hypoxia and epidermal growth factor receptor in non-small-cell lung cancer.

Swinson DE, O'Byrne KJ.

St James's Hospital, Dublin, Ireland.

Tumor hypoxia has been recognized to confer resistance to anticancer therapy since the early 20th century. More recently, its fundamental role in tumorigenesis has been established. Hypoxia-inducible factor (HIF)-1 has been identified as an important transcription factor that mediates the cellular response to hypoxia, promoting both cellular survival and apoptosis under different conditions. Increased tumor cell expression of this transcription factor promotes tumor growth in vivo and is associated with a worse prognosis in patients with non-small-cell lung cancer (NSCLC) undergoing tumor resection. The epidermal growth factor receptor (EGFR) promotes tumor cell proliferation and angiogenesis and inhibits apoptosis. Epidermal growth factor receptor expression increases in a stepwise manner during tumorigenesis and is overexpressed in > 50% of NSCLC tumors. This review discusses the reciprocal relationship between tumor cell hypoxia and EGFR. Recent studies suggest that hypoxia induces expression of EGFR and its ligands. In return, EGFR might enhance the cellular response to hypoxia by increasing expression of HIF-1a and so act as a survival factor for hypoxic cancer cells. Immunohistochemical studies on a series of resected NSCLC tumors add weight to this contention by demonstrating a close association between expression of EGFR, HIF-1a, and 1 of HIF-1's target proteins, carbonic anhydrase IX. In this article we discuss emerging treatment strategies for NSCLC that target HIF-1, HIF-1 transcriptional targets, and EGFR.

Publication Types:

PMID: 16512978 [PubMed - indexed for MEDLINE]


2: Breast Cancer Res. 2000;2(3):203-10. Epub 2000 Mar 7.

Tyrosine kinase signalling in breast cancer: epidermal growth factor receptor and c-Src interactions in breast cancer.

Biscardi JS, Ishizawar RC, Silva CM, Parsons SJ.

Department of Microbiology and Cancer Center, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, USA.

Both the non-receptor tyrosine kinase, c-Src, and members of the epidermal growth factor (EGF) receptor family are overexpressed in high percentages of human breast cancers. Because these molecules are plasma membrane-associated and involved in mitogenesis, it has been speculated that they function in concert with one another to promote breast cancer development and progression. Evidence to date supports a model wherein c-Src potentiates the survival, proliferation and tumorigenesis of EGF receptor family members, in part by associating with them. Phosphorylation of the EGF receptor by c-SRC is also critical for mitogenic signaling initiated by the EGF receptor itself, as well as by several G-protein coupled receptors (GPCRs), a cytokine receptor, and the estrogen receptor. Thus, c-Src appears to have pleiotropic effects on cancer cells by modulating the action of multiple growth-promoting receptors.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

PMID: 11250711 [PubMed - indexed for MEDLINE]


3: Clin Cancer Res. 1998 Apr;4(4):821-8.

Interactions between the epidermal growth factor receptor and type I protein kinase A: biological significance and therapeutic implications.

Ciardiello F, Tortora G.

Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Facoltą di Medicina e Chirurgia, Universitą di Napoli Federico II, Italy.

Peptide growth factors regulate normal cellular proliferation and differentiation through autocrine and paracrine pathways and are involved in cancer development and progression. Among the endogenous growth factors, the epidermal growth factor (EGF)-related proteins play an important role in the pathogenesis of human cancer. In fact, overexpression of EGF-related growth factors such as transforming growth factor alpha and amphiregulin and/or their specific receptor, the EGF receptor (EGFR), has been detected in several types of human cancers, including breast, lung, and colorectal cancers. Therefore, the blockade of EGFR activation by using anti-EGFR monoclonal antibodies (MAbs) has been proposed as a potential anticancer therapy. The cAMP-dependent protein kinase (PKA) is an intracellular enzyme with serine-threonine kinase activity that plays a key role in cell growth and differentiation. Two PKA isoforms with identical catalytic (C) subunits but different cAMP-binding regulatory (R) subunits (defined as RI in PKAI and RII in PKAII) have been identified. Predominant expression of PKAII is found in normal nonproliferating tissues and in growth-arrested cells, whereas enhanced levels of PKAI are detected steadily in tumor cells and transiently in normal cells exposed to mitogenic stimuli. Overexpression of PKAI has been correlated recently with poor prognosis in breast cancer patients. Inhibition of PKAI expression and function by specific pharmacological agents such as the selective cAMP analogue 8-chloro-cAMP (8-Cl-cAMP) induces growth inhibition in various human cancer cell lines in vitro and in vivo. We have provided experimental evidence of a functional cross-talk between ligand-induced EGFR activation and PKAI expression and function. In fact, PKAI is overexpressed and activated following transforming growth factor alpha-induced transformation in several rodent and human cell line models. Furthermore, PKAI is involved in the intracellular mitogenic signaling following ligand-induced EGFR activation. We have shown that an interaction between EGFR and PKAI occurs through direct binding of the RI subunit to the Grb2 adaptor protein. In this respect, PKAI seems to function downstream of the EGFR, and experimental evidence suggests that PKAI is acting upstream of the mitogen-activated protein kinase pathway. We have also demonstrated that the functional interaction between the EGFR and the PKAI pathways could have potential therapeutic implications. In fact, the combined interference with both EGFR and PKAI with specific pharmacological agents, such as anti-EGFR blocking MAbs and cAMP analogues, has a cooperative antiproliferative effect on human cancer cell lines in vitro and in vivo. The antitumor activity of this combination could be explored in a clinical setting because both the 8-Cl-cAMP analogue and the anti-EGFR blocking MAb C225 have entered human clinical trial evaluation. Finally, both MAb C225 and 8-Cl-cAMP are specific inhibitors of intracellular mitogenic signaling that have different mechanisms of action compared with conventional cytotoxic drugs. In this respect, a cooperative growth-inhibitory effect in combination with several chemotherapeutic agents in a large series of human cancer cell lines in vitro and in vivo has been demonstrated for anti-EGFR blocking MAbs or for 8-Cl-cAMP. Therefore, the combination of MAb C225 and 8-Cl-cAMP following chemotherapy could be investigated in cancer patients.

Publication Types:
Research Support, Non-U.S. Gov't

PMID: 9563874 [PubMed - indexed for MEDLINE]

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