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


METHODS
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.
Lonardo
Fulvio
F
Harper Hospital, Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Dragnev
Konstantin H
KH
Freemantle
Sarah J
SJ
Ma
Yan
Y
Memoli
Natalie
N
Sekula
David
D
Knauth
Elisabeth A
EA
Beebe
Jean S
JS
Dmitrovsky
Ethan
E
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D008938:Mitosis; D009602:Nitrosamines / Q000633:toxicity; D019000:Phosphotyrosine / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014212:Tretinoin / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D002273:Carcinogens; D017931:DNA Primers; D009602:Nitrosamines; D019938:Cyclin D1; D019000:Phosphotyrosine; D014212:Tretinoin; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D066246:ErbB Receptors