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

• Published in: Clinical cancer research Vol. 12; no. 7; pp. 2281 - 2288
• Main Authors: Merrick, Daniel T., Kittelson, John, Winterhalder, Ralph, Kotantoulas, Georgia, Ingeberg, Steen, Keith, Robert L., Kennedy, Timothy C., Miller, York E., Franklin, Wilbur A., Hirsch, Fred R.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.04.2006
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic agents; Biological and medical sciences; Biomarkers, Tumor - analysis; Biomarkers, Tumor - genetics; Biopsy; Bronchial Neoplasms - genetics; Bronchial Neoplasms - pathology; Bronchial Neoplasms - prevention & control; Cell Cycle Proteins - analysis; Cell Cycle Proteins - drug effects; Cell Cycle Proteins - genetics; Cell Proliferation - drug effects; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; cellular proliferation; Chemoprevention; Disease Progression; Female; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; growth factor receptor; Humans; Immunohistochemistry; Ki-67 Antigen - analysis; Ki-67 Antigen - genetics; lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lung Neoplasms - prevention & control; Male; Medical sciences; Middle Aged; Minichromosome Maintenance Complex Component 2; Nuclear Proteins - analysis; Nuclear Proteins - drug effects; Nuclear Proteins - genetics; Pharmacology. Drug treatments; Pneumology; Precancerous Conditions - drug therapy; Precancerous Conditions - genetics; Precancerous Conditions - metabolism; premalignant change; Receptor, Epidermal Growth Factor - biosynthesis; Receptor, Epidermal Growth Factor - drug effects; Receptor, Epidermal Growth Factor - genetics; Receptor, ErbB-2 - biosynthesis; Receptor, ErbB-2 - drug effects; Receptor, ErbB-2 - genetics; Sensitivity and Specificity; Tumors of the respiratory system and mediastinum; Lung disease; Evaluation; Dysplasia; Targeting; Respiratory disease; Lung cancer; erbB2 Gene; Malignant tumor; Anticarcinogen; Gene expression; Respiratory system; Bronchopulmonary; Epidermal growth factor receptor; Human Epidermal growth factor Receptor 2; Respiratory tract; Target; Growth factor receptor; C-Onc gene; Bronchus disease; Protooncogene
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-2291

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.