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.
OBJECTIVE
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.


METHODS
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.
Merrick
Daniel T
DT
Department of Pathology, University of Colorado Cancer Center, Denver, Colorado, USA. Daniel.Merrick@med.va.gov
Kittelson
John
J
Winterhalder
Ralph
R
Kotantoulas
Georgia
G
Ingeberg
Steen
S
Keith
Robert L
RL
Kennedy
Timothy C
TC
Miller
York E
YE
Franklin
Wilbur A
WA
Hirsch
Fred R
FR
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D001706:Biopsy; D001984:Bronchial Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D018797:Cell Cycle Proteins / Q000032:analysis / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018890:Chemoprevention; D018450:Disease Progression; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D064111:Minichromosome Maintenance Complex Component 2; D009687:Nuclear Proteins / Q000032:analysis / Q000187:drug effects / Q000235:genetics; D011230:Precancerous Conditions / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D012680:Sensitivity and Specificity
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D066246:ErbB Receptors; D019394:Ki-67 Antigen; D064111:Minichromosome Maintenance Complex Component 2; D009687:Nuclear Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C084859:MCM2 protein, human