Strain-specific spontaneous and NNK-mediated tumorigenesis in Pten+/- mice.
Pten is a negative regulator of the Akt pathway, and its inactivation is believed to be an etiological factor in many tumor types. Pten+/- mice are susceptible to a variety of spontaneous tumor types, depending on strain background. Pten+/- mice, in lung tumor-sensitive and -resistant background strains, were treated with a tobacco carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), to determine whether allelic Pten deletion can cooperate with NNK in carcinogenesis in lung or other tissues. In lung tumor-resistant C57BL/6 Pten+/- or +/+ mice, NNK treatment did not lead to any lung tumors and did not increase the incidence or severity of tumors previously reported for this strain. In contrast, in a lung tumor-susceptible pseudo-A/J strain, there was a dose-dependent increase in lung tumor size in Pten+/- compared with +/+ mice, although there was no increase in multiplicity. No other tumor types were observed in pseudo-A/J Pten+/- mice regardless of NNK treatment. Lung tumors from these Pten+/- mice had K-ras mutations, retained Pten expression and had similar Akt pathway activation as lung tumors from +/+ mice. Therefore, deletion of a single copy of Pten does not substantially add to the lung tumor phenotype conferred by mutation of K-ras by NNK, and there is likely no selective advantage for loss of the second Pten allele in lung tumor initiation.
Hollander
Mary Christine
MC
Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20889, USA.
Balogh
Andria R
AR
Liwanag
Jaminelli
J
Han
Wei
W
Linnoila
Ritva Ilona
RI
Anver
Miriam R
MR
Dennis
Phillip A
PA
D000483:Alleles; D000818:Animals; D004305:Dose-Response Relationship, Drug; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D011905:Genes, ras / Q000187:drug effects / Q000235:genetics; D007274:Injections, Intraperitoneal; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009602:Nitrosamines / Q000008:administration & dosage; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013045:Species Specificity
D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse