Increased susceptibility to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in transgenic mice overexpressing c-myc and epidermal growth factor in alveolar type II cells.
OBJECTIVE
As previously described, SPC/myc transgenic mice developed bronchioloalveolar adenocarcinomas derived from alveolar type II (AT II) cells within 10-14 months, whereas SPC/IgEGF transgenic mice developed hyperplasias. Our purpose was to determine the potential interplay of environmental and genetic factors in lung tumorigenesis.


METHODS
Six-week-old SPC/myc and SPC/IgEGF transgenic mice, overexpressing c-myc and a secretable form of the epidermal growth factor (IgEGF) under the control of the surfactant protein C (SPC) promoter, were treated with a single dose of the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). As control groups, SPC/myc and SPC/IgEGF transgenic mice were treated with NaCl and non-transgenic littermates were treated with NNK or NaCl, respectively.


RESULTS
After 6 months, none of the NaCl-treated transgenic littermates showed bronchioloalveolar hyperplasia and adenocarcinoma formation, whereas 100% of the NNK-treated SPC/myc transgenic mice did. The effect of NNK on SPC/IgEGF transgenic mice was less pronounced, inducing hyperplasia in the lung in only 16.7% of them. In 90% of the NNK-treated non-transgenic littermates no neoplastic changes were detected in the lung.


CONCLUSIONS
These results demonstrate that the progression of pulmonary bronchioloalveolar adenocarcinomas, induced by expression of c-myc as a transgene, was accelerated by NNK, suggesting that c-myc cooperates with NNK-induced mutations.
Ehrhardt
A
A
Center for Medical Biotechnology, Fraunhofer Institute for Toxicology and Aerosol Research, Nikolai-Fuchs-Strasse 1, 30625, Hannover, Germany. anjae@stanford.edu
Bartels
T
T
Klocke
R
R
Paul
D
D
Halter
R
R
D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D002273:Carcinogens / Q000009:adverse effects*; D004815:Epidermal Growth Factor / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006965:Hyperplasia / Q000139:chemically induced; D036341:Intercellular Signaling Peptides and Proteins; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009602:Nitrosamines / Q000009:adverse effects*; D010455:Peptides / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D037721:Pulmonary Surfactant-Associated Protein C; D011663:Pulmonary Surfactants
D002273:Carcinogens; D036341:Intercellular Signaling Peptides and Proteins; D009602:Nitrosamines; D010455:Peptides; D016271:Proto-Oncogene Proteins c-myc; D037721:Pulmonary Surfactant-Associated Protein C; D011663:Pulmonary Surfactants; C489680:Sftpc protein, mouse; D004815:Epidermal Growth Factor; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone