Correlates and determinants of nuclear epidermal growth factor receptor content in an oropharyngeal cancer tissue microarray

Amanda Psyrri, Brian Egleston, Eirini Pectasides, Paul Maurice Weinberger, Ziwei Yu, Diane Kowalski, Clarence Sasaki, Bruce Haffty, David Rimm, Barbara Burtness

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Background: We have previously reported nuclear localization of epidermal growth factor receptor (EGFR) protein in oropharyngeal cancer tissue. Nuclear EGFR levels were inversely correlated with survival and response to radiotherapy. Here, we sought to identify the determinants and correlates of nuclear EGFR content. Methods: We analyzed an oropharyngeal cancer tissue microarray for the expression of the key molecules of the EGFR signaling cascade using an automated image analysis technique (AQUA) scored on a scale of 0 to 255, which permits protein quantitation and subcellular localization. Patients with oropharyngeal squamous cell cancer treated with radiotherapy or surgery and radiotherapy were eligible. Data were analyzed using Spearman correlations and multiple linear regression with robust SEs. Results: Of the 95 tumors included in this study, 72 (75%) had sufficient tissue for analysis of nuclear EGFR. Nuclear EGFR levels were associated with membranous/cytoplasmic EGFR levels (ρ = 0.82, P < 0.001), nuclear extracellular signal-regulated kinase-2 (ρ = 0.30, ρ = 0.01), and nuclear proliferating cell nuclear antigen (PCNA; ρ = 0.36, P = 0.003). Nuclear phosphorylated-Akt, cyclin D1, phosphatase and tensin homolog (mutated in multiple cancers 1) (PTEN), p53, and proliferation marker Ki-67 levels did not correlate with nuclear EGFR level. In multivariable analysis, only PCNA retained its significant association (P = 0.01). Conclusions: These results are consistent with preclinical data showing that EGFR may function as a tyrosine kinase in the nucleus, phosphorylating and stabilizing PCNA. The nuclear activity of EGFR may constitute a novel therapeutic target.

Original languageEnglish (US)
Pages (from-to)1486-1492
Number of pages7
JournalCancer Epidemiology Biomarkers and Prevention
Volume17
Issue number6
DOIs
StatePublished - Jun 1 2008

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Oropharyngeal Neoplasms
Epidermal Growth Factor Receptor
Proliferating Cell Nuclear Antigen
Radiotherapy
Squamous Cell Neoplasms
Mitogen-Activated Protein Kinase 1
Cyclin D1
Phosphoric Monoester Hydrolases
Protein-Tyrosine Kinases
Linear Models
Neoplasms
Proteins

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

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Correlates and determinants of nuclear epidermal growth factor receptor content in an oropharyngeal cancer tissue microarray. / Psyrri, Amanda; Egleston, Brian; Pectasides, Eirini; Weinberger, Paul Maurice; Yu, Ziwei; Kowalski, Diane; Sasaki, Clarence; Haffty, Bruce; Rimm, David; Burtness, Barbara.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 17, No. 6, 01.06.2008, p. 1486-1492.

Research output: Contribution to journalArticle

Psyrri, A, Egleston, B, Pectasides, E, Weinberger, PM, Yu, Z, Kowalski, D, Sasaki, C, Haffty, B, Rimm, D & Burtness, B 2008, 'Correlates and determinants of nuclear epidermal growth factor receptor content in an oropharyngeal cancer tissue microarray', Cancer Epidemiology Biomarkers and Prevention, vol. 17, no. 6, pp. 1486-1492. https://doi.org/10.1158/1055-9965.EPI-07-2684
Psyrri, Amanda ; Egleston, Brian ; Pectasides, Eirini ; Weinberger, Paul Maurice ; Yu, Ziwei ; Kowalski, Diane ; Sasaki, Clarence ; Haffty, Bruce ; Rimm, David ; Burtness, Barbara. / Correlates and determinants of nuclear epidermal growth factor receptor content in an oropharyngeal cancer tissue microarray. In: Cancer Epidemiology Biomarkers and Prevention. 2008 ; Vol. 17, No. 6. pp. 1486-1492.
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AU - Egleston, Brian

AU - Pectasides, Eirini

AU - Weinberger, Paul Maurice

AU - Yu, Ziwei

AU - Kowalski, Diane

AU - Sasaki, Clarence

AU - Haffty, Bruce

AU - Rimm, David

AU - Burtness, Barbara

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N2 - Background: We have previously reported nuclear localization of epidermal growth factor receptor (EGFR) protein in oropharyngeal cancer tissue. Nuclear EGFR levels were inversely correlated with survival and response to radiotherapy. Here, we sought to identify the determinants and correlates of nuclear EGFR content. Methods: We analyzed an oropharyngeal cancer tissue microarray for the expression of the key molecules of the EGFR signaling cascade using an automated image analysis technique (AQUA) scored on a scale of 0 to 255, which permits protein quantitation and subcellular localization. Patients with oropharyngeal squamous cell cancer treated with radiotherapy or surgery and radiotherapy were eligible. Data were analyzed using Spearman correlations and multiple linear regression with robust SEs. Results: Of the 95 tumors included in this study, 72 (75%) had sufficient tissue for analysis of nuclear EGFR. Nuclear EGFR levels were associated with membranous/cytoplasmic EGFR levels (ρ = 0.82, P < 0.001), nuclear extracellular signal-regulated kinase-2 (ρ = 0.30, ρ = 0.01), and nuclear proliferating cell nuclear antigen (PCNA; ρ = 0.36, P = 0.003). Nuclear phosphorylated-Akt, cyclin D1, phosphatase and tensin homolog (mutated in multiple cancers 1) (PTEN), p53, and proliferation marker Ki-67 levels did not correlate with nuclear EGFR level. In multivariable analysis, only PCNA retained its significant association (P = 0.01). Conclusions: These results are consistent with preclinical data showing that EGFR may function as a tyrosine kinase in the nucleus, phosphorylating and stabilizing PCNA. The nuclear activity of EGFR may constitute a novel therapeutic target.

AB - Background: We have previously reported nuclear localization of epidermal growth factor receptor (EGFR) protein in oropharyngeal cancer tissue. Nuclear EGFR levels were inversely correlated with survival and response to radiotherapy. Here, we sought to identify the determinants and correlates of nuclear EGFR content. Methods: We analyzed an oropharyngeal cancer tissue microarray for the expression of the key molecules of the EGFR signaling cascade using an automated image analysis technique (AQUA) scored on a scale of 0 to 255, which permits protein quantitation and subcellular localization. Patients with oropharyngeal squamous cell cancer treated with radiotherapy or surgery and radiotherapy were eligible. Data were analyzed using Spearman correlations and multiple linear regression with robust SEs. Results: Of the 95 tumors included in this study, 72 (75%) had sufficient tissue for analysis of nuclear EGFR. Nuclear EGFR levels were associated with membranous/cytoplasmic EGFR levels (ρ = 0.82, P < 0.001), nuclear extracellular signal-regulated kinase-2 (ρ = 0.30, ρ = 0.01), and nuclear proliferating cell nuclear antigen (PCNA; ρ = 0.36, P = 0.003). Nuclear phosphorylated-Akt, cyclin D1, phosphatase and tensin homolog (mutated in multiple cancers 1) (PTEN), p53, and proliferation marker Ki-67 levels did not correlate with nuclear EGFR level. In multivariable analysis, only PCNA retained its significant association (P = 0.01). Conclusions: These results are consistent with preclinical data showing that EGFR may function as a tyrosine kinase in the nucleus, phosphorylating and stabilizing PCNA. The nuclear activity of EGFR may constitute a novel therapeutic target.

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