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Evidence for the Epidermal Growth Factor Receptor As a Target for Lung Cancer Prevention¹

Harper Hospital, Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan 48201 [F. L.]; Departments of Pharmacology and Toxicology [K. H. D., S. J. F., Y. M., N. M., D. S., E. D.], Medicine [K. H. D., E. D.], and Pathology [N. M.], and the Norris Cotton Cancer Center [K. H. D., E. D.], Dartmouth Medical School, Hanover, New Hampshire 03755; and Pfizer Global Research and Development, Groton, Connecticut 06340 [E. A. K., J. S. B.]

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.

Commentary

Lung Cancer Prevention: Retinoids and the Epidermal Growth Factor Receptor—A Phoenix Rising?

Steven D. Averbuch
Clin. Cancer Res. 2002 8: 1-3. [Full Text] [PDF]

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