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Evidence for the epidermal growth factor receptor as a target for lung cancer prevention
Fulvio Lonardo1, Konstantin H Dragnev, Sarah J Freemantle
1Harper Hospital, Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Purpose:
There is a need to identify lung cancer prevention mechanisms. All-trans-retinoic acid (RA) was reported previously to inhibit N-nitrosamine-4-(methylnitrosamino)-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-2B(NNK) cells, and retinoid chemoprevented BEAS-2B(NNK 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 expression. 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.
Insights
All-trans-retinoic acid (RA) prevents lung cancer by inhibiting epidermal growth factor receptor (EGFR) overexpression in bronchial cells exposed to the carcinogen N-nitrosamine-4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone (NNK). This chemoprevention targets EGFR, crucial for cell growth and preventing cancerous transformation.
Area of Science:
- Oncology
- Cell Biology
- Chemoprevention Research
Background:
- Epidermal growth factor receptor (EGFR) overexpression is common in non-small cell lung cancers (NSCLC) and bronchial preneoplasia.
- All-trans-retinoic acid (RA) has demonstrated inhibitory effects on the carcinogenic transformation of human bronchial epithelial cells induced by N-nitrosamine-4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone (NNK).
Purpose of the Study:
- To identify the specific molecular pathways targeted by RA during its chemopreventive action against NNK-induced bronchial cell transformation.
- To investigate the role of EGFR in NNK-induced carcinogenesis and its modulation by RA treatment.
Main Methods:
- BEAS-2B human bronchial epithelial cells, NNK-transformed cells, and RA-treated NNK-transformed cells were analyzed for EGFR expression.
- Reporter plasmid activity was assessed to determine if RA directly regulated EGFR expression.
- The effects of RA on epidermal growth factor (EGF)-induced EGFR-phosphotyrosine levels, cyclin D1 expression, and mitogenesis were evaluated.
Main Results:
- NNK-mediated transformation of BEAS-2B cells led to increased EGFR expression.
- RA treatment repressed EGFR expression and reporter plasmid activity, and reduced EGF-dependent mitogenesis, EGFR-associated phosphotyrosine levels, and cyclin D1 expression.
- RA prevented the transformation and outgrowth of EGFR-overexpressing cells, even after NNK exposure, with p53-induced species appearing before EGFR elevation post-NNK exposure.
Conclusions:
- EGFR is implicated as a key chemoprevention target in the carcinogen-exposed bronchial epithelium.
- Effective chemoprevention, like RA treatment, can prevent bronchial epithelial cell transformation by inhibiting the selection of EGFR-overexpressing cells, particularly when genomic damage repair mechanisms are insufficient.