Epigenetic inactivation of EGFR by CpG island hypermethylation in cancer.
The epidermal growth factor receptor (EGFR) is a member of the HER/ERB-B family of transmembrane receptor kinases. Overexpression of EGFR confers advantages in cell proliferation, survival, and migration and correlates with decreased survival in multiple solid tumors. However, a proportion of these malignancies have little or no expression of EGFR. CpG island hypermethylation and associated transcriptional silencing are common in solid tumors. The methylation status of the EGFR CpG island was examined in a series of cell lines and tissues. Dense EGFR methylation (90%) was found in the breast cancer cell line CAMA1, and a moderate degree of methylation (30-50%) was observed in the breast cancer cell lines MB435 and MB453. Transcriptional silencing of EGFR in these cell lines closely correlated with methylation. By contrast, no methylation of the HER-2/ neu CpG island was detected. EGFR hypermethylation was also found in a subset of unselected primary breast (20%), head and neck squamous cell carcinoma (35%), and lung tumors (11%). Treatment with decitabine resulted in the reexpression of EGFR in CAMA1 and MB453. Both cell lines are relatively resistant to killing by the EGFR inhibitor gefitinib. However, after cotreatment with decitabine and gefitinib, a significant effect on the induction of apoptosis was observed. In conclusion, EGFR is hypermethylated and silenced in a subset of solid tumor cell lines and primary tumor specimens, and cotreatment with decitabine and gefitinib has an additive effect only in EGFR methylated breast cancer cell lines.
Montero
Alberto J
AJ
Division of Hematology-Oncology, Medical University of South Carolina, Charleston, South Carolina, USA.
Díaz-Montero
C Marcela
CM
Mao
Li
L
Youssef
Emile M
EM
Estecio
Marcos
M
Shen
Lanlan
L
Issa
Jean-Pierre J
JP
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D019175:DNA Methylation; D017931:DNA Primers; D000077209:Decitabine; D015226:Dinucleoside Phosphates / Q000235:genetics*; D044127:Epigenesis, Genetic; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D009928:Organ Specificity; D011799:Quinazolines / Q000627:therapeutic use; D015183:Restriction Mapping; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D001374:Azacitidine; D017931:DNA Primers; D000077209:Decitabine; D015226:Dinucleoside Phosphates; D066246:ErbB Receptors; D000077156:Gefitinib; D011799:Quinazolines; C015772:CpG dinucleotide