Correlates and determinants of nuclear epidermal growth factor receptor content in an oropharyngeal cancer tissue microarray.
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 (rho = 0.82, P < 0.001), nuclear extracellular signal-regulated kinase-2 (rho = 0.30, P = 0.01), and nuclear proliferating cell nuclear antigen (PCNA; rho = 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.
Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut, USA.
Amanda
A
Psyrri
Brian
B
Egleston
Paul
P
Weinberger
Ziwei
Z
Yu
Diane
D
Kowalski
Clarence
C
Sasaki
Bruce
B
Haffty
David
D
Rimm
Barbara
B
Burtness
D000704:Analysis of Variance; D014408:Biomarkers, Tumor / Q000378:metabolism; D002467:Cell Nucleus / Q000737:chemistry*; D066246:ErbB Receptors / Q000096:biosynthesis*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007124:Immunoenzyme Techniques; D016014:Linear Models; D009959:Oropharyngeal Neoplasms / Q000378:metabolism* / Q000628:therapy; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D018709:Statistics, Nonparametric
D014408:Biomarkers, Tumor; D018809:Proliferating Cell Nuclear Antigen; D066246:ErbB Receptors