Evidence for the epidermal growth factor receptor as a target for lung cancer prevention

Fulvio Lonardo, Konstantin H. Dragnev, Sarah J. Freemantle, Yan Ma, Natalie Memoli, David Sekula, Konstantin H. Dragnev, Ethan Dmitrovsky, Natalie Memoli, Konstantin H. Dragnev, Ethan Dmitrovsky, Elisabeth A. Knauth, Jean S. Beebe

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: There is a need to identify lung cancer prevention mechanisms. All-trans-retinoic acid (RA) was reported previously to inhibit N-nitrosamine-4-(methyl-nitrosamino)-1-(3 pyridyl)-1-butanone (NNK) carcinogenic transformation of BEAS-2B human bronchial epithelial cells (J. Langenfeld et al., Oncogene, 13: 1983-1990, 1996). This study was undertaken to identify pathways targeted during this chemoprevention. Experimental Design: Because epidermal growth factor receptor (EGFR) overexpression is frequent in non-small cell lung cancers (NSCLC) and bronchial preneoplasia, BEAS-2B cells, carcinogen-transformed BEAS-2BNNK cells, and retinoid chemoprevented BEAS-2BNNK RA cells were each examined for EGFR expression. Whether RA treatment regulated directly EGFR expression or reporter plasmid activity was studied. RA effects on epidermal growth factor (EGF) induction of EGFR-phosphotyrosine levels, cyclin D1 expression and mitogenesis were examined in BEAS-2B cells. Results: Findings reveal that NNK-mediated transformation of BEAS-2B cells increased EGFR expression. RA treatment repressed EGFR expression and reporter plasmid activity in these cells. This treatment reduced EGF-dependent mitogenesis as well as EGFR-associated phosphotyrosine levels and cyclin D1. These findings extend prior work by highlighting EGFR as a chemoprevention target in the lung. Notably, RA treatment prevented transformation as well as outgrowth of EGFR overexpressing bronchial epithelial cells, despite NNK exposure. After acute NNK exposure, p53-induced species that appear after DNA damage or oxidative stress were evident before an observed increase in EGFR expression. Conclusions: These findings indicate how effective chemoprevention prevents carcinogenic transformation of bronchial epithelial cells when repair of genomic damage does not select against EGFR overexpressing cells. This implicates EGFR as a chemoprevention target in the carcinogen-exposed bronchial epithelium.

Original languageEnglish (US)
Pages (from-to)54-60
Number of pages7
JournalClinical Cancer Research
Volume8
Issue number1
StatePublished - 2002
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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