Nuclear EGFR as a molecular target in cancer

doi:10.1016/j.radonc.2013.06.010

Radiotherapy and Oncology

Volume 108, Issue 3, September 2013, Pages 370-377

https://doi.org/10.1016/j.radonc.2013.06.010 Get rights and content

Abstract

The epidermal growth factor receptor (EGFR) has been one of the most targeted receptors in the field of oncology. While anti-EGFR inhibitors have demonstrated clinical success in specific cancers, most patients demonstrate either intrinsic or acquired resistance within one year of treatment. Many mechanisms of resistance to EGFR inhibitors have been identified, one of these being attributed to alternatively localized EGFR from the cell membrane into the cell’s nucleus. Inside the nucleus, EGFR functions as a co-transcription factor for several genes involved in cell proliferation and angiogenesis, and as a tyrosine kinase to activate and stabilize proliferating cell nuclear antigen and DNA dependent protein kinase. Nuclear localized EGFR is highly associated with disease progression, worse overall survival in numerous cancers, and enhanced resistance to radiation, chemotherapy, and the anti-EGFR therapies gefitinib and cetuximab. In this review the current knowledge of how nuclear EGFR enhances resistance to cancer therapeutics is discussed, in addition to highlighting ways to target nuclear EGFR as an anti-cancer strategy in the future.

Section snippets

The role of nuclear EGFR in resistance to cancer therapeutics

Intrinsic and acquired tumor cell resistance to both conventional and targeted cancer therapies remains one of the largest obstacles to overcome clinically. While nuclear EGFR is observed in cells of high proliferative origin, numerous reports describe increased nuclear localization of EGFR in models of cancer resistance to different therapeutic regimes [28], [29], [37], [38], [39]. These studies identified that nuclear EGFR could enhance resistance by influencing DNA damage repair, DNA

Future prospective of the nuclear RTK field

From the identification of nuclear localized EGFR in highly proliferative tissues to the uncovering of its vibrant roles in enhancing tumorigenic processes, the field of nuclear HER family receptors has blossomed over the past ten years. Even with the exposé of over 50 articles citing the presence and/or functions of nuclear EGFR in cancer, this field is still in its infancy. Studies have yet to show that nuclear EGFR functions as a true oncogene separate from its membrane-localized

Cell lines

The human HNSCC cell lines SCC1, SCC6, and SCC1483 were kindly supplied by Dr. T. Carey (University of Michigan, MI, USA) [75]. The human breast cancer cell lines SKBr3, MDAMB468, and SUM229 were kindly supplied by Dr. J. Boerner (Wayne State University School of Medicine, Karmanos Cancer Institute, MI, USA) [76]. The human MCF-7 and hamster CHOK1 cells were purchased from ATCC (Manassas, VA, USA). All cell lines were maintained in their respective media with 10% fetal bovine serum and 1%

Competing of interests

The authors declare no competing interests.

Authors’ contributions

TMB and DLW performed the literature search and drafted the manuscript. TMB and MI performed all experimentation depicted in this manuscript. All authors provided critical review of the manuscript and approved the final draft.

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ReviewNuclear EGFR as a molecular target in cancer

Abstract

Section snippets

The role of nuclear EGFR in resistance to cancer therapeutics

Future prospective of the nuclear RTK field

Cell lines

Competing of interests

Authors’ contributions

Untangling the ErbB signalling network

Nat Rev Mol Cell Biol

The scent of Nobel Prize success

Funct Neurol

Signal transduction and oncogenesis by ErbB/HER receptors

Int J Radiat Oncol Biol Phys

Amplification and overexpression of the EGF receptor gene in primary human glioblastomas

J Cell Sci Suppl

Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin

Nature

Expression of epidermal growth factor receptors in human brain tumors

Cancer Res

Epidermal growth factor receptors in non-small cell lung cancer

Br J Cancer

Epidermal growth factor receptor gene amplification and expression in head and neck cancer cell lines

Head Neck

Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors

Mol Biol Med

Growth stimulation of A431 cells by epidermal growth factor: identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody

Proc Natl Acad Sci USA

Monoclonal antibody against epidermal growth factor receptor is internalized without stimulating receptor phosphorylation

Proc Natl Acad Sci USA

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

Discov Med

Nuclear trafficking of the epidermal growth factor receptor family membrane proteins

Oncogene

Landscape of EGFR signaling network in human cancers: biology and therapeutic response in relation to receptor subcellular locations

Cancer Lett

The translocon Sec61beta localized in the inner nuclear membrane transports membrane-embedded EGF receptor to the nucleus

J Biol Chem

COPI-mediated retrograde trafficking from the Golgi to the ER regulates EGFR nuclear transport

Biochem Biophys Res Commun

Nuclear-cytoplasmic transport of EGFR involves receptor endocytosis, importin beta1 and CRM1

J Cell Biochem

Role of the Sec61 translocon in EGF receptor trafficking to the nucleus and gene expression

Mol Biol Cell

Characterization of a novel tripartite nuclear localization sequence in the EGFR family

J Biol Chem

Membrane-bound trafficking regulates nuclear transport of integral epidermal growth factor receptor (EGFR) and ErbB-2

J Biol Chem

Activation of c-fos gene expression by a kinase-deficient epidermal growth factor receptor

Mol Cell Biol

Nuclear localization of EGF receptor and its potential new role as a transcription factor

Nat Cell Biol

Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway

Cancer Cell

Co-regulation of B-Myb expression by E2F1 and EGF receptor

Mol Carcinog

Cyclooxygenase-2 is a novel transcriptional target of the nuclear EGFR–STAT3 and EGFRvIII–STAT3 signaling axes

Mol Cancer Res

Nuclear epidermal growth factor receptor (EGFR) interacts with signal transducer and activator of transcription 5 (STAT5) in activating Aurora-A gene expression

Nucleic Acids Res

A functional nuclear epidermal growth factor receptor, SRC and stat3 heteromeric complex in pancreatic cancer cells

Plos One

Nuclear translocation of epidermal growth factor receptor by Akt-dependent phosphorylation enhances breast cancer-resistant protein expression in gefitinib-resistant cells

J Biol Chem

Inhibition of radiation-induced EGFR nuclear import by C225 (Cetuximab) suppresses DNA-PK activity

Radiother Oncol

Radiation-induced epidermal growth factor receptor nuclear import is linked to activation of DNA-dependent protein kinase

J Biol Chem

Quantitative determination of nuclear and cytoplasmic epidermal growth factor receptor expression in oropharyngeal squamous cell cancer by using automated quantitative analysis

Clin Cancer Res

Novel prognostic value of nuclear epidermal growth factor receptor in breast cancer

Cancer Res

Nuclear expression of epidermal growth factor receptor is a novel prognostic value in patients with ovarian cancer

Mol Carcinog

Nuclear expression of phosphorylated EGFR is associated with poor prognosis of patients with esophageal squamous cell carcinoma

Pathobiology

EGFR nuclear import in gallbladder carcinoma: nuclear phosphorylated EGFR upregulates iNOS expression and confers independent prognostic impact

Ann Surg Oncol

Nuclear EGFR expression predicts poor survival in resected non-small cell lung cancer

J Thorac Oncol

Review
Nuclear EGFR as a molecular target in cancer