Skip to main content

Advertisement

SpringerLink
Log in

EGFR signaling pathway in breast cancers: from traditional signal transduction to direct nuclear translocalization

  • Review
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Summary

Aberrant epidermal growth factor receptor (EGFR) signaling is a major characteristic of many human malignancies including breast cancer. Since the discovery of EGF in 1960’s and its receptor in 1980’s, our understanding of the EGF/EGFR pathway has been significantly advanced and consequently, EGFR is considered as a major oncogenic factor and an attractive therapeutic target. The well-established traditional function of EGFR is known to transmit extra-cellular mitogenic signals, such as EGF and transforming growth factor-α (TGF-α), through activating a number of downstream signaling cascades. These include signaling modules that involve phospholipase C-γ, Ras, and phosphatidylinositol-3 kinase (PI-3K). In cancer cells, the common outcomes following the activation of the EGFR-mediated downstream pathways are altered gene activities, leading to un-controlled tumor proliferation and apoptosis. Interestingly, emerging evidences suggest the existence of a direct mode of the EGFR pathway that is distinct from the traditional transduction pathway. This new mode of EGFR signaling involves cellular transport of EGFR from the cell-surface to the cell nucleus, association of nuclear EGFR complex with gene promoters, and transcriptional regulation of the target genes. Although the nature and pathological consequences of the nuclear EGFR pathway remain elusive, accumulating evidences suggest its association with increased tumor cell proliferation and poor survival rate in breast cancer patients. While several anti-EGFR agents are being tested in breast cancer patients clinically and others under pre-clinical development, a better understanding of the traditional and the nuclear EGFR pathways will facilitate the identification of patients that are likely to respond to these agents as well as future development of more effective anti-EGFR therapeutic interventions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Cohen S, (1962). Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal J Biol Chem 237:1555–1562

    PubMed  CAS  Google Scholar 

  2. Gregory H, (1975). Isolation and structure of urogastrone and its relationship to epidermal growth factor Nature 257:325–327

    Article  PubMed  CAS  Google Scholar 

  3. Cohen S, Carpenter G, (1975). Human epidermal growth factor: isolation and chemical and biological properties Proc Natl Acad Sci USA 72:1317–1321

    PubMed  CAS  Google Scholar 

  4. Cohen S, Carpenter G, King L Jr., (1980). Epidermal growth factor-receptor-protein kinase interactions. Co-purification of receptor and epidermal growth factor-enhanced phosphorylation activity J Biol Chem 255:4834–4842

    PubMed  CAS  Google Scholar 

  5. Cohen S, Ushiro H, Stoscheck C, Chinkers M, (1982). A native 170,000 epidermal growth factor receptor-kinase complex from shed plasma membrane vesicles J Biol Chem 257:1523–1531

    PubMed  CAS  Google Scholar 

  6. Cohen S, Carpenter G, King L Jr., (1981). Epidermal growth factor-receptor-protein kinase interactions Prog Clin Biol Res 66(Pt A):557–567

    PubMed  Google Scholar 

  7. Cohen S, Fava RA, Sawyer ST, (1982). Purification and characterization of epidermal growth factor receptor/protein kinase from normal mouse liver Proc Natl Acad Sci USA 79:6237–6241

    PubMed  CAS  Google Scholar 

  8. Sporn MB, Todaro GJ, (1980). Autocrine secretion and malignant transformation of cells N Engl J Med 303:878–880

    PubMed  CAS  Google Scholar 

  9. Arteaga Ca, (2003). Targeting HER1/EGFR: A molecular approach to cancer therapy Seminars in Oncology 30:3–14

    CAS  Google Scholar 

  10. Gill GN, Kawamoto T, Cochet C, Le A, Sato JD, Masui H, McLeod C, Mendelsohn J, (1984). Monoclonal anti-epidermal growth factor receptor antibodies which are inhibitors of epidermal growth factor binding and antagonists of epidermal growth factor binding and antagonists of epidermal growth factor-stimulated tyrosine protein kinase activity J Biol Chem 259:7755–7760

    PubMed  CAS  Google Scholar 

  11. Sato JD, Kawamoto T, Le AD, Mendelsohn J, Polikoff J, Sato GH, (1983). Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors Mol Biol Med 1:511–529

    PubMed  CAS  Google Scholar 

  12. Patnaik A, Beeram M, de Bono JS, Mita A, Chu SC, Rowinsky EK, Schwartz G, O’Rourke P, Takimoto CH, Tolcher AW: Phase I and Pharmacokinetics (PK) of Combined erbB1 and erbB2 Blockade with OSI-774 (Erlotinib; E) and Trastuzumab (T) in Combination with Weekly Paclitaxel (P) in Patients (pts) with Advanced Solid Tumors. Proceedings of American Society of Clinical Oncology Annual Meeting, Abstract No: 2000, 2005

  13. Polychronis A, Sinnett HD, Hadjiminas D, Singhal H, Mansi JL, Ali S, Slade MJ, Shousha S, Morrisson K, Coombes RC: Anti-proliferative and molecular effects of neoadjuvant (pre-operative) gefitinib alone or in combination with anastrozole in epidermal growth factor receptor (EGFR) positive, estrogen receptor alpha (ERa) positive patients with primary breast cancer. Proceedings of American Society of Clinical Oncology Annual Meeting, Abstract No: 552, 2005

  14. Ciardiello F, Troiani T, Caputo F, de Laurentiis M, Tortora G, Palmieri G, de Vita F, Colantuoni G, de Placido S, Bianco A: Phase II trial of gefitinib combined with docetaxel as first-line therapy in patients with metastatic breast cancer. Proceedings of American Society of Clinical Oncology Annual Meeting, Abstract No: 3080, 2005

  15. Graham DL, Hillman DW, Hobday TJ, Rousey SR, Nair SG, Soori GS, Sabagh TM, Perez EA: N0234: Phase II study of erlotinib (OSI-774) plus gemcitabine as first-or second-line therapy for metastatic breast cancer (MBC). Proceedings of American Society of Clinical Oncology Annual Meeting, Abstract No: 644, 2005

  16. Arteaga CL, Baselga J, (2004). Tyrosine kinase inhibitors: why does the current process of clinical development not apply to them? Cancer Cell 5:525–531

    Article  PubMed  CAS  Google Scholar 

  17. Twombly R, (2005). Failing survival advantage in crucial trial, future of Iressa is in jeopardy J Natl Cancer Inst 97:249–250

    Article  PubMed  Google Scholar 

  18. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA, (2004). Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib N Engl J Med 350:2129–2139

    Article  PubMed  CAS  Google Scholar 

  19. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M, (2004). EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy Science 304:1497–1500

    Article  PubMed  CAS  Google Scholar 

  20. Sordella R, Bell DW, Haber DA, Settleman J, (2004). Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways Science 305:1163–1167

    Article  PubMed  CAS  Google Scholar 

  21. Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H, (2004). EGF receptor gene mutations are common in lung cancers from ‘never smokers’ and are associated with sensitivity of tumors to gefitinib and erlotinib Proc Natl Acad Sci USA 101:13306–13311

    PubMed  CAS  Google Scholar 

  22. Chou TY, Chiu CH, Li LH, Hsiao CY, Tzen CY, Chang KT, Chen YM, Perng RP, Tsai SF, Tsai CM, (2005). Mutation in the tyrosine kinase domain of epidermal growth factor receptor is a predictive and prognostic factor for gefitinib treatment in patients with non-small cell lung cancer Clin Cancer Res 11:3750–3757

    Article  PubMed  CAS  Google Scholar 

  23. Lee JW, Soung YH, Kim SY, Nam HK, Park WS, Nam SW, Kim MS, Sun DI, Lee YS, Jang JJ, Lee JY, Yoo NJ, Lee SH, (2005). Somatic mutations of EGFR gene in squamous cell carcinoma of the head and neck Clin Cancer Res 11:2879–2882

    Article  PubMed  CAS  Google Scholar 

  24. Marie Y, Carpentier AF, Omuro AM, Sanson M, Thillet J, Hoang-Xuan K, Delattre JY, (2005). EGFR tyrosine kinase domain mutations in human gliomas Neurology 64:1444–1445

    PubMed  CAS  Google Scholar 

  25. Su MC, Lien HC, Jeng YM, (2005). Absence of epidermal growth factor receptor exon 18–21 mutation in hepatocellular carcinoma Cancer Lett 224:117–121

    PubMed  CAS  Google Scholar 

  26. Cohen S, Taylor JM, (1974). Epidermal growth factor: chemical and biological characterization Recent Prog Horm Res 30:533–550

    PubMed  CAS  Google Scholar 

  27. Haigler HT, McKanna JA, Cohen S, (1979). Direct visualization of the binding and internalization of a ferritin conjugate of epidermal growth factor in human carcinoma cells A-431 J Cell Biol 81:382–395

    Article  PubMed  CAS  Google Scholar 

  28. Carpenter G, (2003). ErbB-4: mechanism of action and biology Exp Cell Res 284:66–77

    Article  PubMed  CAS  Google Scholar 

  29. Park OK, Schaefer TS, Nathans D, (1996). In vitro activation of Stat3 by epidermal growth factor receptor kinase Proc Natl Acad Sci U S A 93:13704–13708

    Article  PubMed  CAS  Google Scholar 

  30. Bowman T, Broome MA, Sinibaldi D, Wharton W, Pledger WJ, Sedivy JM, Irby R, Yeatman T, Courtneidge SA, Jove R, (2001). Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis Proc Natl Acad Sci USA 98:7319–7324

    Article  PubMed  CAS  Google Scholar 

  31. Barre B, Avril S, Coqueret O, (2003). Opposite regulation of myc and p21waf1 transcription by STAT3 proteins J Biol Chem 278:2990–2996

    Article  PubMed  CAS  Google Scholar 

  32. Anderson D, Koch CA, Grey L, Ellis C, Moran MF, Pawson T, (1990). Binding of SH2 domains of phospholipase C gamma 1, GAP, and Src to activated growth factor receptors Science 250:979–982

    PubMed  CAS  Google Scholar 

  33. Navolanic PM, Steelman LS, McCubrey JA, (2003). EGFR family signaling and its association with breast cancer development and resistance to chemotherapy (Review) Int J Oncol 22:237–252

    PubMed  CAS  Google Scholar 

  34. Bowman T, Garcia R, Turkson J, Jove R, (2000). STATs in oncogenesis Oncogene 19:2474–2488

    Article  PubMed  CAS  Google Scholar 

  35. Bacus SS, Chin D, Yarden Y, Zelnick CR, Stern DF, (1996). Type 1 receptor tyrosine kinases are differentially phosphorylated in mammary carcinoma and differentially associated with steroid receptors Am J Pathol 148:549–558

    PubMed  CAS  Google Scholar 

  36. Craven RJ, Lightfoot H, Cance WG, (2003). A decade of tyrosine kinases: from gene discovery to therapeutics Surg Oncol 12:39–49

    Article  PubMed  Google Scholar 

  37. Baselga J, Norton L, (2002). Focus on breast cancer Cancer Cell 1:319–322

    Article  PubMed  CAS  Google Scholar 

  38. Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, Darnell JE Jr., (1999). Stat3 as an oncogene Cell 98:295–303

    Article  PubMed  CAS  Google Scholar 

  39. Petrocelli T, Slingerland JM, (2001). PTEN deficiency: a role in mammary carcinogenesis Breast Cancer Res 3:356–360

    Article  PubMed  CAS  Google Scholar 

  40. Shi W, Zhang X, Pintilie M, Ma N, Miller N, Banerjee D, Tsao MS, Mak T, Fyles A, Liu FF, (2003). Dysregulated PTEN-PKB and negative receptor status in human breast cancer Int J Cancer 104:195–203

    Article  PubMed  CAS  Google Scholar 

  41. Zhou BP, Liao Y, Xia W, Spohn B, Lee MH, Hung MC, (2001). Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells Nat Cell Biol 3:245–252

    Article  PubMed  CAS  Google Scholar 

  42. Zhou BP, Liao Y, Xia W, Zou Y, Spohn B, Hung MC, (2001). HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation Nat Cell Biol 3:973–982

    Article  PubMed  CAS  Google Scholar 

  43. Li Y, Dowbenko D, Lasky LA, (2002). AKT/PKB phosphorylation of p21Cip/WAF1 enhances protein stability of p21Cip/WAF1 and promotes cell survival J Biol Chem 277:11352–11361

    Article  PubMed  CAS  Google Scholar 

  44. Kumar R, Hung MC, (2005). Signaling intricacies take center stage in cancer cells Cancer Res 65:2511–2515

    Article  PubMed  CAS  Google Scholar 

  45. El-Deiry WS, (2001). Akt takes centre stage in cell-cycle deregulation Nat Cell Biol 3:E71–73

    Article  PubMed  CAS  Google Scholar 

  46. Rossig L, Jadidi AS, Urbich C, Badorff C, Zeiher AM, Dimmeler S, (2001). Akt-dependent phosphorylation of p21(Cip1) regulates PCNA binding and proliferation of endothelial cells Mol Cell Biol 21:5644–5657

    Article  PubMed  CAS  Google Scholar 

  47. Huang S, Shu L, Dilling MB, Easton J, Harwood FC, Ichijo H, Houghton PJ, (2003). Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21(Cip1) Mol Cell 11:1491–1501

    Article  PubMed  CAS  Google Scholar 

  48. Xia W, Chen JS, Zhou X, Sun PR, Lee DF, Liao Y, Zhou BP, Hung MC, (2004). Phosphorylation/cytoplasmic localization of p21Cip1/WAF1 is associated with HER2/neu overexpression and provides a novel combination predictor for poor prognosis in breast cancer patients Clin Cancer Res 10:3815–3824

    Article  PubMed  CAS  Google Scholar 

  49. Winters ZE, Hunt NC, Bradburn MJ, Royds JA, Turley H, Harris AL, Norbury CJ, (2001). Subcellular localisation of cyclin B, Cdc2 and p21(WAF1/CIP1) in breast cancer. association with prognosis Eur J Cancer 37:2405–2412

    Article  PubMed  CAS  Google Scholar 

  50. Liang J, Zubovitz J, Petrocelli T, Kotchetkov R, Connor MK, Han K, Lee JH, Ciarallo S, Catzavelos C, Beniston R, Franssen E, Slingerland JM, (2002). PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest Nat Med 8:1153–1160

    PubMed  CAS  Google Scholar 

  51. Shin I, Yakes FM, Rojo F, Shin NY, Bakin AV, Baselga J, Arteaga CL, (2002). PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization Nat Med 8:1145–1152

    Article  PubMed  CAS  Google Scholar 

  52. Viglietto G, Motti ML, Bruni P, Melillo RM, D’Alessio A, Califano D, Vinci F, Chiappetta G, Tsichlis P, Bellacosa A, Fusco A, Santoro M, (2002). Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer Nat Med 8:1136–1144

    Article  PubMed  CAS  Google Scholar 

  53. Clarke RB, (2003). p27KIP1 phosphorylation by PKB/Akt leads to poor breast cancer prognosis Breast Cancer Res 5:162–163

    Article  PubMed  Google Scholar 

  54. Honda R, Tanaka H, Yasuda H, (1997). Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53 FEBS Lett 420:25–27

    Article  PubMed  CAS  Google Scholar 

  55. Knuefermann C, Lu Y, Liu B, Jin W, Liang K, Wu L, Schmidt M, Mills GB, Mendelsohn J, Fan Z, (2003). HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells Oncogene 22:3205–3212

    Article  PubMed  CAS  Google Scholar 

  56. Ogawara Y, Kishishita S, Obata T, Isazawa Y, Suzuki T, Tanaka K, Masuyama N, Gotoh Y, (2002). Akt enhances Mdm2-mediated ubiquitination and degradation of p53 J Biol Chem 277:21843–21850

    Article  PubMed  CAS  Google Scholar 

  57. Mayo LD, Donner DB, (2001). A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus Proc Natl Acad Sci USA 98:11598–11603

    Article  PubMed  CAS  Google Scholar 

  58. Turkson J, Jove R, (2000). STAT proteins: novel molecular targets for cancer drug discovery Oncogene 19:6613–6626

    Article  PubMed  CAS  Google Scholar 

  59. Darnell JE Jr., (1997). STATs and gene regulation Science 277:1630–1635

    Article  PubMed  CAS  Google Scholar 

  60. Yu H, Jove R, (2004). The STATs of cancer–new molecular targets come of age Nat Rev Cancer 4:97–105

    PubMed  CAS  Google Scholar 

  61. Garcia R, Bowman TL, Niu G, Yu H, Minton S, Muro-Cacho CA, Cox CE, Falcone R, Fairclough R, Parsons S, Laudano A, Gazit A, Levitzki A, Kraker A, Jove R, (2001). Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells Oncogene 20:2499–2513

    Article  PubMed  CAS  Google Scholar 

  62. Fernandes A, Hamburger AW, Gerwin BI, (1999). ErbB-2 kinase is required for constitutive stat 3 activation in malignant human lung epithelial cells Int J Cancer 83:564–570

    Article  PubMed  CAS  Google Scholar 

  63. Sriuranpong V, Park JI, Amornphimoltham P, Patel V, Nelkin BD, Gutkind JS, (2003). Epidermal growth factor receptor-independent constitutive activation of STAT3 in head and neck squamous cell carcinoma is mediated by the autocrine/paracrine stimulation of the interleukin 6/gp130 cytokine system Cancer Res 63:2948–2956

    PubMed  CAS  Google Scholar 

  64. Darnell JE Jr, Kerr IM, Stark GR, (1994). Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins Science 264:1415–1421

    PubMed  CAS  Google Scholar 

  65. Fu XY, (1999). From PTK-STAT signaling to caspase expression and apoptosis induction Cell Death Differ 6:1201–1208

    Article  PubMed  CAS  Google Scholar 

  66. Yang E, Lerner L, Besser D, Darnell JE Jr, (2003). Independent and cooperative activation of chromosomal c-fos promoter by STAT3 J Biol Chem 278:15794–15799

    Article  PubMed  CAS  Google Scholar 

  67. Shirogane T, Fukada T, Muller JM, Shima DT, Hibi M, Hirano T, (1999). Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and antiapoptosis Immunity 11:709–719

    Article  PubMed  CAS  Google Scholar 

  68. Sinibaldi D, Wharton W, Turkson J, Bowman T, Pledger WJ, Jove R, (2000). Induction of p21WAF1/CIP1 and cyclin D1 expression by the Src oncoprotein in mouse fibroblasts: role of activated STAT3 signaling Oncogene 19:5419–5427

    Article  PubMed  CAS  Google Scholar 

  69. Karni R, Jove R, Levitzki A, (1999). Inhibition of pp60c-Src reduces Bcl-XL expression and reverses the transformed phenotype of cells overexpressing EGF and HER-2 receptors Oncogene 18:4654–4662

    Article  PubMed  CAS  Google Scholar 

  70. Ivanov VN, Bhoumik A, Krasilnikov M, Raz R, Owen-Schaub LB, Levy D, Horvath CM, Ronai Z, (2001). Cooperation between STAT3 and c-jun suppresses Fas transcription Mol Cell 7:517–528

    Article  PubMed  CAS  Google Scholar 

  71. Lo H-W, Hsu S-C, Ali-Seyed M, Gunduz M, Xia W, Wei Y, Bartholomeusz G, Shih J-Y, Hung M-C: Nuclear Interaction of EGFR and STAT3 in the Activation of iNOS/NO Pathway. Cancer Cell 7: 575–589, 2005

    Google Scholar 

  72. Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, Zhang S, Wang T, Sinibaldi D, Coppola D, Heller R, Ellis LM, Karras J, Bromberg J, Pardoll D, Jove R, Yu H, (2002). Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis Oncogene 21:2000–2008

    Article  PubMed  CAS  Google Scholar 

  73. Wei D, Le X, Zheng L, Wang L, Frey JA, Gao AC, Peng Z, Huang S, Xiong HQ, Abbruzzese JL, Xie K, (2003). Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis Oncogene 22:319–329

    Article  PubMed  CAS  Google Scholar 

  74. Gray MJ, Zhang J, Ellis LM, Semenza GL, Evans DB, Watowich SS, Gallick GE, (2005). HIF-1alpha, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas Oncogene 24:3110–3120

    Article  PubMed  CAS  Google Scholar 

  75. Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S, Bhattacharya R, Gabrilovich D, Heller R, Coppola D, Dalton W, Jove R, Pardoll D, Yu H, (2004). Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells Nat Med 10:48–54

    Article  PubMed  CAS  Google Scholar 

  76. Nam S, Buettner R, Turkson J, Kim D, Cheng JQ, Muehlbeyer S, Hippe F, Vatter S, Merz KH, Eisenbrand G, Jove R, (2005). Indirubin derivatives inhibit Stat3 signaling and induce apoptosis in human cancer cells Proc Natl Acad Sci USA 102:5998–6003

    Article  PubMed  CAS  Google Scholar 

  77. Turkson J, Zhang S, Palmer J, Kay H, Stanko J, Mora LB, Sebti S, Yu H, Jove R, (2004). Inhibition of constitutive signal transducer and activator of transcription 3 activation by novel platinum complexes with potent antitumor activity Mol Cancer Ther 3:1533–1542

    PubMed  CAS  Google Scholar 

  78. Marti U, Burwen SJ, Wells A, Barker ME, Huling S, Feren AM, Jones AL, (1991). Localization of epidermal growth factor receptor in hepatocyte nuclei Hepatology 13:15–20

    Article  PubMed  CAS  Google Scholar 

  79. Marti U, Hug M, (1995). Acinar and cellular distribution and mRNA expression of the epidermal growth factor receptor are changed during liver regeneration J Hepatol 23:318–327

    PubMed  CAS  Google Scholar 

  80. Marti U, Ruchti C, Kampf J, Thomas GA, Williams ED, Peter HJ, Gerber H, Burgi U, (2001). Nuclear localization of epidermal growth factor and epidermal growth factor receptors in human thyroid tissues Thyroid 11:137–145

    Article  PubMed  CAS  Google Scholar 

  81. Marti U, Wells A, (2000). The nuclear accumulation of a variant epidermal growth factor receptor (EGFR) lacking the transmembrane domain requires coexpression of a full-length EGFR Mol Cell Biol Res Commun 3:8–14

    Article  PubMed  CAS  Google Scholar 

  82. Raper SE, Burwen SJ, Barker ME, Jones AL, (1987). Translocation of epidermal growth factor to the hepatocyte nucleus during rat liver regeneration Gastroenterology 92:1243–1250

    PubMed  CAS  Google Scholar 

  83. Schausberger E, Eferl R, Parzefall W, Chabicovsky M, Breit P, Wagner EF, Schulte-Hermann R, Grasl-Kraupp B, Chabikovsky M, (2003). Induction of DNA synthesis in primary mouse hepatocytes is associated with nuclear pro-transforming growth factor alpha and erbb-1 and is independent of c-jun Carcinogenesis 24:835–841

    Article  PubMed  CAS  Google Scholar 

  84. Lin SY, Makino K, Xia W, Matin A, Wen Y, Kwong KY, Bourguignon L, Hung MC, (2001). Nuclear localization of EGF receptor and its potential new role as a transcription factor Nat Cell Biol 3:802–808

    Article  PubMed  CAS  Google Scholar 

  85. Kamio T, Shigematsu K, Sou H, Kawai K, Tsuchiyama H, (1990). Immunohistochemical expression of epidermal growth factor receptors in human adrenocortical carcinoma Hum Pathol 21:277–282

    Article  PubMed  CAS  Google Scholar 

  86. Lipponen P, Eskelinen M, (1994). Expression of epidermal growth factor receptor in bladder cancer as related to established prognostic factors, oncoprotein (c-erbB-2, p53) expression and long-term prognosis Br J Cancer 69:1120–1125

    PubMed  CAS  Google Scholar 

  87. Lo H-W, Xia W, Wei Y, Ali-Seyed M, Huang SF, Hung M-C, (2005). Novel prognostic value of nuclear EGF receptor in breast cancer Cancer Res 65:338–348

    PubMed  CAS  Google Scholar 

  88. Bourguignon L, Lan K-H, Singleton P, Lin S-Y, Yu D, Hung M-C, (2002). Localizing the EGF receptor – Reply Nat Cell Biol 4:E22–E23

    Article  PubMed  Google Scholar 

  89. Klein C, Gensburger C, Freyermuth S, Nair BC, Labourdette G, Malviya AN, (2004). A 120 kDa nuclear phospholipase Cgamma1 protein fragment is stimulated in vivo by EGF signal phosphorylating nuclear membrane EGFR Biochemistry 43:15873–15883

    Article  PubMed  CAS  Google Scholar 

  90. Ni CY, Murphy MP, Golde TE, Carpenter G, (2001). Gamma-secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase Science 294:2179–2181

    Article  PubMed  CAS  Google Scholar 

  91. Offterdinger M, Schofer C, Weipoltshammer K, Grunt TW, (2002). c-erbB-3: a nuclear protein in mammary epithelial cells J Cell Biol 157:929–939

    Article  PubMed  CAS  Google Scholar 

  92. Xie Y, Hung MC, (1994). Nuclear localization of p185neu tyrosine kinase and its association with transcriptional transactivation Biochem Biophys Res Commun 203:1589–1598

    Article  PubMed  CAS  Google Scholar 

  93. Wang SC, Lien HC, Xia W, Chen IF, Lo HW, Wang Z, Ali-Seyed M, Lee DF, Bartholomeusz G, Ou-Yang F, Giri DK, Hung MC, (2004). Binding at and transactivation of the COX-2 promoter by nuclear tyrosine kinase receptor ErbB-2 Cancer Cell 6:251–261

    Article  PubMed  CAS  Google Scholar 

  94. Krolewski JJ, (2005). Cytokine and growth factor receptors in the nucleus: What’s up with that? J Cell Biochem 95:478–487

    Article  PubMed  CAS  Google Scholar 

  95. Ni CY, Yuan H, Carpenter G, (2003). Role of the ErbB-4 carboxyl terminus in gamma-secretase cleavage J Biol Chem 278:4561–4565

    Article  PubMed  CAS  Google Scholar 

  96. Cheng QC, Tikhomirov O, Zhou W, Carpenter G: Ectodomain cleavage of ErbB-4: Characterization of the cleavage site and m80 fragment. J Biol Chem, 278: 38421–38427, 2003

    Google Scholar 

  97. Carpenter G, (2003). Nuclear localization and possible functions of receptor tyrosine kinases Curr Opin Cell Biol 15:143–148

    Article  PubMed  CAS  Google Scholar 

  98. Rakowicz-Szulczynska EM, Herlyn M, Koprowski H, (1988). Nerve growth factor receptors in chromatin of melanoma cells, proliferating melanocytes, and colorectal carcinoma cells in vitro Cancer Res 48:7200–7206

    PubMed  CAS  Google Scholar 

  99. Reilly JF, Maher PA, (2001). Importin beta-mediated nuclear import of fibroblast growth factor receptor: role in cell proliferation J Cell Biol 152:1307–1312

    Article  PubMed  CAS  Google Scholar 

  100. Maher PA, (1996). Nuclear Translocation of fibroblast growth factor (FGF) receptors in response to FGF-2 J Cell Biol 134:529–536

    Article  PubMed  CAS  Google Scholar 

  101. Raabe TD, Deadwyler G, Varga JW, Devries GH, (2004). Localization of neuregulin isoforms and erbB receptors in myelinating glial cells Glia 45:197–207

    Article  PubMed  Google Scholar 

  102. Podlecki DA, Smith RM, Kao M, Tsai P, Huecksteadt T, Brandenburg D, Lasher RS, Jarett L, Olefsky JM, (1987). Nuclear translocation of the insulin receptor A possible mediator of insulin’s long term effects J Biol Chem 262:3362–3368

    PubMed  CAS  Google Scholar 

  103. Zhang FX, Lai CH, Lai SK, Yung KK, Shum DK, Chan YS, (2003). Neurotrophin receptor immunostaining in the vestibular nuclei of rats Neuroreport 14:851–855

    Article  PubMed  CAS  Google Scholar 

  104. Zwaagstra JC, Guimond A, O’Connor-McCourt MD, (2000). Predominant intracellular localization of the type I transforming growth factor-beta receptor and increased nuclear accumulation after growth arrest Exp Cell Res 258:121–134

    Article  PubMed  CAS  Google Scholar 

  105. Chan YS, Chen LW, Lai CH, Shum DK, Yung KK, Zhang FX, (2003). Receptors of glutamate and neurotrophin in vestibular neuronal functions J Biomed Sci 10:577–587

    PubMed  CAS  Google Scholar 

  106. Stachowiak EK, Maher PA, Tucholski J, Mordechai E, Joy A, Moffett J, Coons S, Stachowiak MK, (1997). Nuclear accumulation of fibroblast growth factor receptors in human glial cells association with cell proliferation Oncogene 14:2201–2211

    Article  PubMed  CAS  Google Scholar 

  107. Pillai G, Cook N, Turley H, Leek RD, Blasquez C, Pezzella F, Harris AL, Gatter KC, (2005). The expression and cellular localization of phosphorylated VEGFR2 in lymphoma and non-neoplastic lymphadenopathy: an immunohistochemical study Histopathology 46:209–216

    Article  PubMed  CAS  Google Scholar 

  108. Jans DA, Hassan G, (1998). Nuclear targeting by growth factors, cytokines, and their receptors: a role in signaling? Bioessays 20:400–411

    Article  PubMed  CAS  Google Scholar 

  109. Bader T, Weitzerbin J, (1994). Nuclear accumulation of interferon gamma Proc Natl Acad Sci USA 91:11831–11835

    PubMed  CAS  Google Scholar 

  110. Larkin J, 3rd, Johnson HM, Subramaniam PS, (2000). Differential nuclear localization of the IFNGR-1 and IFNGR-2 subunits of the IFN-gamma receptor complex following activation by IFN-gamma J Interferon Cytokine Res 20:565–576

    Article  PubMed  CAS  Google Scholar 

  111. Subramaniam PS, Green MM, Larkin J 3rd, Torres BA, Johnson HM, (2001). Nuclear translocation of IFN-gamma is an intrinsic requirement for its biologic activity and can be driven by a heterologous nuclear localization sequence J Interferon Cytokine Res 21:951–959

    Article  PubMed  CAS  Google Scholar 

  112. Subramaniam PS, Johnson HM, (2002). Lipid microdomains are required sites for the selective endocytosis and nuclear translocation of IFN-gamma, its receptor chain IFN-gamma receptor-1, and the phosphorylation and nuclear translocation of STAT1alpha J Immunol 169:1959–1969

    PubMed  CAS  Google Scholar 

  113. Jans DA, Briggs LJ, Gustin SE, Jans P, Ford S, Young IG, (1997). The cytokine interleukin-5 (IL-5) effects cotransport of its receptor subunits to the nucleus in vitro FEBS Lett 410:368–372

    Article  PubMed  CAS  Google Scholar 

  114. Curtis BM, Widmer MB, deRoos P, Qwarnstrom EE, (1990). IL-1 and its receptor are translocated to the nucleus J Immunol 144:1295–1303

    PubMed  CAS  Google Scholar 

  115. Subramaniam PS, Johnson HM, (2004). The IFNAR1 subunit of the type I IFN receptor complex contains a functional nuclear localization sequence FEBS Lett 578:207–210

    Article  PubMed  CAS  Google Scholar 

  116. Grasl-Kraupp B, Schausberger E, Hufnagl K, Gerner C, Low-Baselli A, Rossmanith W, Parzefall W, Schulte-Hermann R, (2002). A novel mechanism for mitogenic signaling via pro-transforming growth factor alpha within hepatocyte nuclei Hepatology 35:1372–1380

    Article  PubMed  CAS  Google Scholar 

  117. Kimura H, (1993). Schwannoma-derived growth factor must be transported into the nucleus to exert its mitogenic activity Proc Natl Acad Sci USA 90:2165–2169

    PubMed  CAS  Google Scholar 

  118. Williams CC, Allison JG, Vidal GA, Burow ME, Beckman BS, Marrero L, Jones FE, (2004). The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone J Cell Biol 167:469–478

    Article  PubMed  CAS  Google Scholar 

  119. Klijn JG, Berns PM, Schmitz PI, Foekens JA, (1992). The clinical significance of epidermal growth factor receptor (EGFR) in human breast cancer: a review on 5232 patients Endocr Rev 13:3–17

    Article  PubMed  CAS  Google Scholar 

  120. Ferrero JM, Ramaioli A, Largillier R, Formento JL, Francoual M, Ettore F, Namer M, Milano G, (2001). Epidermal growth factor receptor expression in 780 breast cancer patients: a reappraisal of the prognostic value based on an eight-year median follow-up Ann Oncol 12:841–846

    Article  PubMed  CAS  Google Scholar 

  121. Seshadri R, McLeay WR, Horsfall DJ, McCaul K, (1996). Prospective study of the prognostic significance of epidermal growth factor receptor in primary breast cancer Int J Cancer 69:23–27

    Article  PubMed  CAS  Google Scholar 

  122. Nicholson RI, Gee JM, Harper ME, (2001). EGFR and cancer prognosis Eur J Cancer 37(Suppl 4):S9–S15

    Article  PubMed  CAS  Google Scholar 

  123. Jenkins DC, Charles IG, Thomsen LL, Moss DW, Holmes LS, Baylis SA, Rhodes P, Westmore K, Emson PC, Moncada S, (1995). Roles of nitric oxide in tumor growth Proc Natl Acad Sci USA 92:4392–4396

    PubMed  CAS  Google Scholar 

  124. Lala PK, Orucevic A, (1998). Role of nitric oxide in tumor progression: lessons from experimental tumors Cancer Metastasis Rev 17:91–106

    Article  PubMed  CAS  Google Scholar 

  125. Vakkala M, Kahlos K, Lakari E, Paakko P, Kinnula V, Soini Y, (2000). Inducible nitric oxide synthase expression, apoptosis, and angiogenesis in in situ and invasive breast carcinomas Clin Cancer Res 6:2408–2416

    PubMed  CAS  Google Scholar 

  126. Ekmekcioglu S, Ellerhorst J, Smid CM, Prieto VG, Munsell M, Buzaid AC, Grimm EA, (2000). Inducible nitric oxide synthase and nitrotyrosine in human metastatic melanoma tumors correlate with poor survival Clin Cancer Res 6:4768–4775

    PubMed  CAS  Google Scholar 

  127. Cianchi F, Cortesini C, Fantappie O, Messerini L, Schiavone N, Vannacci A, Nistri S, Sardi I, Baroni G, Marzocca C, Perna F, Mazzanti R, Bechi P, Masini E, (2003). Inducible nitric oxide synthase expression in human colorectal cancer: correlation with tumor angiogenesis Am J Pathol 162:793–801

    PubMed  CAS  Google Scholar 

  128. Komuro A, Nagai M, Navin NE, Sudol M, (2003). WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus J Biol Chem 278:33334–33341

    Article  PubMed  CAS  Google Scholar 

  129. Reguly T, Wrana JL, (2003). In or out? The dynamics of Smad nucleocytoplasmic shuttling Trends Cell Biol 13:216–220

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA

    Hui-Wen Lo, Sheng-Chieh Hsu & Mien-Chie Hung

  2. Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, Texas, 77030, USA

    Mien-Chie Hung

Authors
  1. Hui-Wen Lo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sheng-Chieh Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mien-Chie Hung
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mien-Chie Hung.

Additional information

Address for offprints and correspondence: Dr. Mien-Chie Hung, Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030, USA; Tel.: 713-792-3668; E-mail: mhung@mdanderson.org

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lo, HW., Hsu, SC. & Hung, MC. EGFR signaling pathway in breast cancers: from traditional signal transduction to direct nuclear translocalization. Breast Cancer Res Treat 95, 211–218 (2006). https://doi.org/10.1007/s10549-005-9011-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-005-9011-0

Keywords

Search

Navigation