title: Life-span inhalation exposure to mainstream cigarette smoke induces lung cancer in B6C3F1 mice through genetic and epigenetic pathways.
abstract: Although cigarette smoke has been epidemiologically associated with lung cancer in humans for many years, animal models of cigarette smoke-induced lung cancer have been lacking. This study demonstrated that life time whole body exposures of female B6C3F1 mice to mainstream cigarette smoke at 250 mg total particulate matter/m(3) for 6 h per day, 5 days a week induces marked increases in the incidence of focal alveolar hyperplasias, pulmonary adenomas, papillomas and adenocarcinomas. Cigarette smoke-exposed mice (n = 330) had a 10-fold increase in the incidence of hyperplastic lesions, and a 4.6-fold (adenomas and papillomas), 7.25-fold (adenocarcinomas) and 5-fold (metastatic pulmonary adenocarcinomas) increase in primary lung neoplasms compared with sham-exposed mice (n = 326). Activating point mutations in codon 12 of the K-ras gene were identified at a similar rate in tumors from sham-exposed mice (47%) and cigarette smoke-exposed mice (60%). The percentages of transversion and transition mutations were similar in both the groups. Hypermethylation of the death associated protein (DAP)-kinase and retinoic acid receptor (RAR)-beta gene promoters was detected in tumors from both sham- and cigarette smoke-exposed mice, with a tendency towards increased frequency of RAR-beta methylation in the tumors from the cigarette smoke-exposed mice. These results emphasize the importance of the activation of K-ras and silencing of DAP-kinase and RAR-beta in lung cancer development, and confirm the relevance of this mouse model for studying lung tumorigenesis.
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, NM 87108, USA. jhutt@lrri.org
authors.forename: Julie A
authors.initials: JA
authors.lastname: Hutt
authors.forename: Brian R
authors.initials: BR
authors.lastname: Vuillemenot
authors.forename: Edward B
authors.initials: EB
authors.lastname: Barr
authors.forename: Marcie J
authors.initials: MJ
authors.lastname: Grimes
authors.forename: Fletcher F
authors.initials: FF
authors.lastname: Hahn
authors.forename: Charles H
authors.initials: CH
authors.lastname: Hobbs
authors.forename: Thomas H
authors.initials: TH
authors.lastname: March
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Gigliotti
authors.forename: Steven K
authors.initials: SK
authors.lastname: Seilkop
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Finch
authors.forename: Joe L
authors.initials: JL
authors.lastname: Mauderly
authors.forename: Steven A
authors.initials: SA
authors.lastname: Belinsky
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics / Q000556:secondary; D000236:Adenoma / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D000280:Administration, Inhalation; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001835:Body Weight; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases; D005260:Female; D020868:Gene Silencing / Q000187:drug effects*; D011905:Genes, ras / Q000187:drug effects; D006965:Hyperplasia / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D015994:Incidence; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D009929:Organ Size; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018168:Receptors, Retinoic Acid / Q000235:genetics; D012907:Smoking / Q000009:adverse effects*; D015996:Survival Rate
chemical_list: D051017:Apoptosis Regulatory Proteins; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases