Gene expression studies demonstrate that the K-ras/Erk MAP kinase signal transduction pathway and other novel pathways contribute to the pathogenesis of cumene-induced lung tumors.
National Toxicology Program (NTP) inhalation studies demonstrated that cumene significantly increased the incidence of alveolar/bronchiolar adenomas and carcinomas in B6C3F1 mice. Cumene or isopropylbenzene is a component of crude oil used primarily in the production of phenol and acetone. The authors performed global gene expression analysis to distinguish patterns of gene regulation between cumene-induced tumors and normal lung tissue and to look for patterns based on the presence or absence of K-ras and p53 mutations in the tumors. Principal component analysis segregated the carcinomas into groups with and without K-ras mutations, but failed to separate the tumors based on p53 mutation status. Expression of genes associated with the Erk MAP kinase signaling pathway was significantly altered in carcinomas with K-ras mutations compared to tumors without K-ras mutations or normal lung. Gene expression analysis also suggested that cumene-induced carcinomas with K-ras mutations have greater malignant potential than those without mutations. In addition, significance analysis of function and expression (SAFE) demonstrated expression changes of genes regulated by histone modification in carcinomas with K-ras mutations. The gene expression analysis suggested the formation of alveolar/bronchiolar carcinomas in cumene-exposed mice typically involves mutation of K-ras, which results in increased Erk MAP kinase signaling and modification of histones.
Wakamatsu
Nobuko
N
Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Collins
Jennifer B
JB
Parker
Joel S
JS
Tessema
Mathewos
M
Clayton
Natasha P
NP
Ton
Thai-Vu T
TV
Hong
Hue-Hua L
HH
Belinsky
Steven
S
Devereux
Theodora R
TR
Sills
Robert C
RC
Lahousse
Stephanie A
SA
D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D000818:Animals; D001555:Benzene Derivatives / Q000633:toxicity*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics*; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology
D001555:Benzene Derivatives; C015763:cumene; D020928:Mitogen-Activated Protein Kinases