title: Strain-specific spontaneous and NNK-mediated tumorigenesis in Pten+/- mice.
abstract: 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.
authors.affiliation: Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20889, USA.
authors.forename: Mary Christine
authors.initials: MC
authors.lastname: Hollander
authors.forename: Andria R
authors.initials: AR
authors.lastname: Balogh
authors.forename: Jaminelli
authors.initials: J
authors.lastname: Liwanag
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.forename: Ritva Ilona
authors.initials: RI
authors.lastname: Linnoila
authors.forename: Miriam R
authors.initials: MR
authors.lastname: Anver
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Dennis
mesh_terms: 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
chemical_list: 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