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Journal Article

The nuclear epidermal growth factor receptor signaling network and its role in cancer

01 Nov 2011-Discovery Medicine (Discov Med)-Vol. 12, Iss: 66, pp 419-432
TL;DR: The current knowledge of the nuclear EGFR signaling network is summarized, including how it is trafficked to the nucleus, the functions it serves inThe nucleus, and how these functions impact cancer progression, survival, and response to chemotherapeutics.
Abstract: The epidermal growth factor receptor (EGFR) is a member of the EGFR family of receptor tyrosine kinases (RTKs). EGFR activation via ligand binding results in signaling through various pathways ultimately resulting in cellular proliferation, survival, angiogenesis, invasion, and metastasis. Aberrant expression or activity of EGFR has been strongly linked to the etiology of several human epithelial cancers including but not limited to head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), breast cancer, pancreatic cancer, and brain cancer. Thus intense efforts have been made to inhibit the activity of EGFR by designing antibodies against the ligand binding domains (cetuximab and panitumumab) or small molecules against the tyrosine kinase domain (erlotinib, gefitinib, and lapatinib). Although targeting membrane-bound EGFR has shown benefit, a new and emerging role for EGFR is now being elucidated. In this review we will summarize the current knowledge of the nuclear EGFR signaling network, including how it is trafficked to the nucleus, the functions it serves in the nucleus, and how these functions impact cancer progression, survival, and response to chemotherapeutics.
Citations
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Journal ArticleDOI
TL;DR: The canonical ligand‐induced EGFR signaling pathway is reviewed, with particular emphasis to its regulation by endocytosis and subversion in human tumors, and the most recent advances in uncovering noncanonical EGFR functions in stress‐induced trafficking, autophagy, and energy metabolism are focused on.

775 citations


Cites background from "The nuclear epidermal growth factor..."

  • ...Translocation of full-length EGFR into the nucleus has long been documented and the functions it has at this location have been extensively investigated; we therefore refer the readers to detailed reviews (Brand et al., 2011; Han and Lo, 2012)....

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Journal ArticleDOI
TL;DR: The preclinical and clinical performance of these dual-targeting approaches are described, the key mechanisms that mediate their increased efficacy and highlights areas for ongoing investigation are discussed.
Abstract: Many therapeutic agents target the ERBB family of receptor tyrosine kinases in various cancers. This Opinion article describes our latest understanding of the value of combining inhibitors directed towards an individual ERBB family member, including the molecular mechanisms of synergy and progress in clinical trials.

368 citations

Journal ArticleDOI
TL;DR: The hypothesis that selected patients with HER2-positive tumors may not need chemotherapy, and more-complete blockade of HER receptors and ER is an effective strategy worthy of further study is supported.
Abstract: Purpose We previously reported the eradication of human epidermal growth factor receptor 2 (HER2)– amplified human xenografts in mice by inhibition of the HER2 pathway with lapatinib and trastuzumab to block all homo- and heterodimer signaling as well as by blockade of estrogen receptor (ER) when expressed. In this clinical trial, we sought to translate these findings to patients using targeted therapy without chemotherapy.

220 citations

Journal ArticleDOI
TL;DR: The current knowledge of how nuclear EGFR enhances resistance to cancer therapeutics is discussed, in addition to highlighting ways to targetnuclear EGFR as an anti-cancer strategy in the future.

202 citations

Journal ArticleDOI
TL;DR: The functions of nuclear EGFR family and the potential pathways by which EGFR is trafficked from the cell surface to a variety of cellular organelles are summarized.
Abstract: Accumulating evidence suggests that various diseases, including many types of cancer, result from alteration of subcellular protein localization and compartmentalization. Therefore, it is worthwhile to expand our knowledge in subcellular trafficking of proteins, such as epidermal growth factor receptor (EGFR) and ErbB-2 of the receptor tyrosine kinases, which are highly expressed and activated in human malignancies and frequently correlated with poor prognosis. The well-characterized trafficking of cell surface EGFR is routed, via endocytosis and endosomal sorting, to either the lysosomes for degradation or back to the plasma membrane for recycling. A novel nuclear mode of EGFR signaling pathway has been gradually deciphered in which EGFR is shuttled from the cell surface to the nucleus after endocytosis, and there, it acts as a transcriptional regulator, transmits signals, and is involved in multiple biological functions, including cell proliferation, tumor progression, DNA repair and replication, and chemo- and radio-resistance. Internalized EGFR can also be transported from the cell surface to several intracellular compartments, such as the Golgi apparatus, the endoplasmic reticulum, and the mitochondria, in addition to the nucleus. In this review, we will summarize the functions of nuclear EGFR family and the potential pathways by which EGFR is trafficked from the cell surface to a variety of cellular organelles. A better understanding of the molecular mechanism of EGFR trafficking will shed light on both the receptor biology and potential therapeutic targets of anti-EGFR therapies for clinical application.

140 citations


Cites background from "The nuclear epidermal growth factor..."

  • ...A full-length form of cell surface EGFR has been shown to be translocated to the nucleus, where evidence suggests that it is involved in transcriptional regulation, cell proliferation, DNA replication, DNA repair, and chemo- and radio-resistance [43-48]....

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References
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Journal ArticleDOI
TL;DR: Survival analyses on a subcohort of patients with locally advanced breast cancer uniformly treated in a prospective study showed significantly different outcomes for the patients belonging to the various groups, including a poor prognosis for the basal-like subtype and a significant difference in outcome for the two estrogen receptor-positive groups.
Abstract: The purpose of this study was to classify breast carcinomas based on variations in gene expression patterns derived from cDNA microarrays and to correlate tumor characteristics to clinical outcome. A total of 85 cDNA microarray experiments representing 78 cancers, three fibroadenomas, and four normal breast tissues were analyzed by hierarchical clustering. As reported previously, the cancers could be classified into a basal epithelial-like group, an ERBB2-overexpressing group and a normal breast-like group based on variations in gene expression. A novel finding was that the previously characterized luminal epithelial/estrogen receptor-positive group could be divided into at least two subgroups, each with a distinctive expression profile. These subtypes proved to be reasonably robust by clustering using two different gene sets: first, a set of 456 cDNA clones previously selected to reflect intrinsic properties of the tumors and, second, a gene set that highly correlated with patient outcome. Survival analyses on a subcohort of patients with locally advanced breast cancer uniformly treated in a prospective study showed significantly different outcomes for the patients belonging to the various groups, including a poor prognosis for the basal-like subtype and a significant difference in outcome for the two estrogen receptor-positive groups.

10,791 citations


"The nuclear epidermal growth factor..." refers result in this paper

  • ...Based on previous reports demonstrating that basal type breast cancers overexpress EGFR and B-Myb(Nielsen et al., 2004; Sorlie et al., 2001), Hanada et al....

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Journal ArticleDOI
31 May 1984-Nature
TL;DR: The complete 1,210-amino acid sequence of the human epidermal growth factor (EGF) receptor precursor, deduced from cDNA clones derived from placental and A431 carcinoma cells, reveals close similarity between the entire predicted ν-erb-B mRNA oncogene product and the receptor transmembrane and cytoplasmic domains.
Abstract: The complete 1,210-amino acid sequence of the human epidermal growth factor (EGF) receptor precursor, deduced from cDNA clones derived from placental and A431 carcinoma cells, reveals close similarity between the entire predicted v-erb-B mRNA oncogene product and the receptor transmembrane and cytoplasmic domains. A single transmembrane region of 23 amino acids separates the extracellular EGF binding and cytoplasmic domains. The receptor gene is amplified and apparently rearranged in A431 cells, generating a truncated 2.8-kilobase mRNA which encodes only the extracellular EGF binding domain.

2,657 citations


"The nuclear epidermal growth factor..." refers background in this paper

  • ...In the 1980s, the EGFR was cloned and sequenced and subsequently recognized as a receptor tyrosine kinase (RTK) (Ullrich et al., 1984)....

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Journal ArticleDOI
TL;DR: A panel of four antibodies (ER, HER1, HER2, and cytokeratin 5/6) can accurately identify basal-like tumors using standard available clinical tools and shows high specificity.
Abstract: Purpose: Expression profiling studies classified breast carcinomas into estrogen receptor (ER)+/luminal, normal breast-like, HER2 overexpressing, and basal-like groups, with the latter two associated with poor outcomes. Currently, there exist clinical assays that identify ER+/luminal and HER2-overexpressing tumors, and we sought to develop a clinical assay for breast basal-like tumors. Experimental Design: To identify an immunohistochemical profile for breast basal-like tumors, we collected a series of known basal-like tumors and tested them for protein patterns that are characteristic of this subtype. Next, we examined the significance of these protein patterns using tissue microarrays and evaluated the prognostic significance of these findings. Results: Using a panel of 21 basal-like tumors, which was determined using gene expression profiles, we saw that this subtype was typically immunohistochemically negative for estrogen receptor and HER2 but positive for basal cytokeratins, HER1, and/or c-KIT. Using breast carcinoma tissue microarrays representing 930 patients with 17.4-year mean follow-up, basal cytokeratin expression was associated with low disease-specific survival. HER1 expression was observed in 54% of cases positive for basal cytokeratins ( versus 11% of negative cases) and was associated with poor survival independent of nodal status and size. c-KIT expression was more common in basal-like tumors than in other breast cancers but did not influence prognosis. Conclusions: A panel of four antibodies (ER, HER1, HER2, and cytokeratin 5/6) can accurately identify basal-like tumors using standard available clinical tools and shows high specificity. These studies show that many basal-like tumors express HER1, which suggests candidate drugs for evaluation in these patients.

2,562 citations


"The nuclear epidermal growth factor..." refers result in this paper

  • ...Based on previous reports demonstrating that basal type breast cancers overexpress EGFR and B-Myb(Nielsen et al., 2004; Sorlie et al., 2001), Hanada et al....

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Journal ArticleDOI
TL;DR: The isolation of the factor responsible for the earlier development of the incisors and eyelids is reported here, a heat-stable, nondialysable, antigenic protein, whose most distinctive chemical characteristic is the absence of phenylalanine and lysine.

2,109 citations


"The nuclear epidermal growth factor..." refers background in this paper

  • ...In the early 1960s Stanley Cohen isolated and characterized a protein from the salivary gland that induced eye-lid opening and tooth eruption in newborn mice(Cohen, 1962)....

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Journal ArticleDOI
TL;DR: It is demonstrated that nuclear EGFR is strongly correlated with highly proliferating activities of tissues and associated with promoter region of cyclin D1 in vivo, suggesting that EGFR might function as a transcription factor to activate genes required for highly proliferationating activities.
Abstract: Epidermal growth factor receptor (EGFR) has been detected in the nucleus in many tissues and cell lines. However, the potential functions of nuclear EGFR have largely been overlooked. Here we demonstrate that nuclear EGFR is strongly correlated with highly proliferating activities of tissues. When EGFR was fused to the GAL4 DNA-binding domain, we found that the carboxy terminus of EGFR contained a strong transactivation domain. Moreover, the receptor complex bound and activated AT-rich consensus-sequence-dependent transcription, including the consensus site in cyclin D1 promoter. By using chromatin immunoprecipitation assays, we further demonstrated that nuclear EGFR associated with promoter region of cyclin D1 in vivo. EGFR might therefore function as a transcription factor to activate genes required for highly proliferating activities.

1,051 citations


"The nuclear epidermal growth factor..." refers background in this paper

  • ...Nuclear expression of EGFR was further detected in other cell types and tissues, such as mouse uterus, developing mouse embryos, rat liver, placentas, thyroids and immortalized epithelial cells of ovary and kidney origins(Cao et al., 1995; Lin et al., 2001; Marti et al., 2001)....

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  • ...Since its first identification of its role as a transcription factor in 2001(Lin et al., 2001), EGFR has led the way in discovery of various other nuclear localized RTKs, including HER2(Wang et al....

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  • ...High levels of EGFR were also found in the nuclei of many tumors, including those of skin, breast, bladder, cervix, adrenocortical carcinoma, thyroid and oral cavity (Kamio et al., 1990; Lin et al., 2001; Lipponen & Eskelinen, 1994; Lo et al., 2005a; Lo et al., 2005b; Marti et al., 2001; Psyrri et al., 2005)....

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  • ...The nuclear counterpart of EGFR appears to be the full-length receptor and likely, in the phosphorylated form, as shown by a number of studies(Cao et al., 1995; Cordero et al., 2002; Dittmann et al., 2005a; Lin et al., 2001; Lo et al., 2005a; Lo et al., 2005b)....

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  • ...EGFR has now been identified as a transcriptional co-activator for seven cancer promoting genes: cyclin D1(Lin et al., 2001), nitric oxide synthase (iNOS)(Lo et al....

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