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Analysis of c-ErbB1/Epidermal Growth Factor Receptor and c-ErbB2/HER-2 Expression in Bronchial Dysplasia: Evaluation of Potential Targets for Chemoprevention of Lung Cancer

Authors' Affiliations: ¹ Departments of Pathology and Medicine/Pulmonary, University of Colorado Cancer Center, ² Departments of Pathology and Medicine/Pulmonary, Denver Veteran's Administration Medical Center, Denver, Colorado, ³ University Hospital, Zurich, Switzerland, ⁴ Athens Chest Hospital, Center of Respiratory and Critical Care Medicine, Athens, Greece, and ⁵ Naestved Hospital, Department of Medicine, Naestved, Denmark

Requests for reprints: Fred R. Hirsch, University of Colorado Health Sciences Center, P.O. Box 6511, Mail Stop 8111, Aurora, CO 80045. Phone: 303-399-8020; Fax: 303-393-5036; E-mail: Daniel.Merrick{at}med.va.gov.

Purpose: Lung cancer is preceded by a premalignant phase during which intervention could decrease associated morbidity and mortality. Molecular characterization of factors involved in controlling progression of bronchial dysplasias will provide markers of premalignant change and identify targets for chemoprevention.

Experimental Design: Immunohistochemical analysis of epidermal growth factor receptor (EGFR; c-ErbB1/EGFR), HER-2/neu (c-ErbB2/HER-2), Ki-67, and minichromosome maintenance protein 2 (MCM2) expression in bronchial dysplasia was undertaken to characterize molecular alterations associated with the progression of these lesions in 268 bronchoscopically obtained biopsies from 134 subjects.

Results: Analysis of biopsies with the most severe diagnosis from each subject showed a linear relationship between increasing marker expression and severity of dysplastic change for EGFR (P < 0.001), Ki-67 (P < 0.001), and MCM2 (P = 0.001) but not HER-2 (P = 0.102). Increased expression of either EGFR or HER-2 was associated with increased levels of Ki-67 and MCM2 expression, and combined overexpression of these receptors was associated with the highest levels of proliferation, suggesting a synergistic effect. Finally, the lack of an associated trend toward increased EGFR expression when comparing the worst and best biopsies within each subject indicated a potential field effect in the induction of EGFR expression.

Conclusions: The results suggest a prominent role for EGFR overexpression in the development and progression of bronchial dysplasia and provide rationale for exploring inhibition of EGFR signaling in lung cancer chemoprevention.

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