A Cyp2a polymorphism predicts susceptibility to NNK-induced lung tumorigenesis in mice

M. Christine Hollander, Xin Zhou, Colleen R. Maier, Andrew D. Patterson, Xinxin Ding, Phillip A. Dennis

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Lung tumors from smokers as well as lung tumors from mice exposed to tobacco carcinogens such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), often carry mutations in K-ras, which activates downstream-signaling pathways such as PI3K/AKT/mTOR pathway. Mice with genetic deletion of one of three isoforms of AKT were used to investigate the role of AKT in mutant K-ras-induced lung tumorigenesis in mice. Although deletion of Akt1 or Akt2 decreased NNK-induced lung tumor formation by 90%, deletion of Akt2 failed to decrease lung tumorigenesis in two other mouse models driven by mutant K-ras. Genetic mapping showed that Akt2 was tightly linked to the cytochrome P450 Cyp2a locus on chromosome 7. Consequently, targeted deletion of Akt2 created linkage to a strain-specific Cyp2a5 polymorphism that decreased activation of NNK in vitro. Mice with this Cyp2a5 polymorphism had decreased NNK-induced DNA adduct formation in vivo and decreased NNK-induced lung tumorigenesis. These studies support human epidemiological studies linking CYP2A polymorphisms with lung cancer risk in humans and highlight the need to confirm phenotypes of genetically engineered mice in multiple mouse strains. Published by Oxford University Press 2011.

Original languageEnglish (US)
Pages (from-to)1279-1284
Number of pages6
JournalCarcinogenesis
Volume32
Issue number8
DOIs
StatePublished - Aug 11 2011
Externally publishedYes

Fingerprint

Carcinogenesis
Lung
Neoplasms
Chromosomes, Human, Pair 7
DNA Adducts
Phosphatidylinositol 3-Kinases
Carcinogens
Cytochrome P-450 Enzyme System
Tobacco
Epidemiologic Studies
Lung Neoplasms
Protein Isoforms
Phenotype
Mutation

ASJC Scopus subject areas

  • Cancer Research

Cite this

Hollander, M. C., Zhou, X., Maier, C. R., Patterson, A. D., Ding, X., & Dennis, P. A. (2011). A Cyp2a polymorphism predicts susceptibility to NNK-induced lung tumorigenesis in mice. Carcinogenesis, 32(8), 1279-1284. https://doi.org/10.1093/carcin/bgr097

A Cyp2a polymorphism predicts susceptibility to NNK-induced lung tumorigenesis in mice. / Hollander, M. Christine; Zhou, Xin; Maier, Colleen R.; Patterson, Andrew D.; Ding, Xinxin; Dennis, Phillip A.

In: Carcinogenesis, Vol. 32, No. 8, 11.08.2011, p. 1279-1284.

Research output: Contribution to journalArticle

Hollander, MC, Zhou, X, Maier, CR, Patterson, AD, Ding, X & Dennis, PA 2011, 'A Cyp2a polymorphism predicts susceptibility to NNK-induced lung tumorigenesis in mice', Carcinogenesis, vol. 32, no. 8, pp. 1279-1284. https://doi.org/10.1093/carcin/bgr097
Hollander, M. Christine ; Zhou, Xin ; Maier, Colleen R. ; Patterson, Andrew D. ; Ding, Xinxin ; Dennis, Phillip A. / A Cyp2a polymorphism predicts susceptibility to NNK-induced lung tumorigenesis in mice. In: Carcinogenesis. 2011 ; Vol. 32, No. 8. pp. 1279-1284.
@article{56c9daa42e374d89880c0e492b08d1da,
title = "A Cyp2a polymorphism predicts susceptibility to NNK-induced lung tumorigenesis in mice",
abstract = "Lung tumors from smokers as well as lung tumors from mice exposed to tobacco carcinogens such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), often carry mutations in K-ras, which activates downstream-signaling pathways such as PI3K/AKT/mTOR pathway. Mice with genetic deletion of one of three isoforms of AKT were used to investigate the role of AKT in mutant K-ras-induced lung tumorigenesis in mice. Although deletion of Akt1 or Akt2 decreased NNK-induced lung tumor formation by 90{\%}, deletion of Akt2 failed to decrease lung tumorigenesis in two other mouse models driven by mutant K-ras. Genetic mapping showed that Akt2 was tightly linked to the cytochrome P450 Cyp2a locus on chromosome 7. Consequently, targeted deletion of Akt2 created linkage to a strain-specific Cyp2a5 polymorphism that decreased activation of NNK in vitro. Mice with this Cyp2a5 polymorphism had decreased NNK-induced DNA adduct formation in vivo and decreased NNK-induced lung tumorigenesis. These studies support human epidemiological studies linking CYP2A polymorphisms with lung cancer risk in humans and highlight the need to confirm phenotypes of genetically engineered mice in multiple mouse strains. Published by Oxford University Press 2011.",
author = "Hollander, {M. Christine} and Xin Zhou and Maier, {Colleen R.} and Patterson, {Andrew D.} and Xinxin Ding and Dennis, {Phillip A.}",
year = "2011",
month = "8",
day = "11",
doi = "10.1093/carcin/bgr097",
language = "English (US)",
volume = "32",
pages = "1279--1284",
journal = "Carcinogenesis",
issn = "0143-3334",
publisher = "Oxford University Press",
number = "8",

}

TY - JOUR

T1 - A Cyp2a polymorphism predicts susceptibility to NNK-induced lung tumorigenesis in mice

AU - Hollander, M. Christine

AU - Zhou, Xin

AU - Maier, Colleen R.

AU - Patterson, Andrew D.

AU - Ding, Xinxin

AU - Dennis, Phillip A.

PY - 2011/8/11

Y1 - 2011/8/11

N2 - Lung tumors from smokers as well as lung tumors from mice exposed to tobacco carcinogens such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), often carry mutations in K-ras, which activates downstream-signaling pathways such as PI3K/AKT/mTOR pathway. Mice with genetic deletion of one of three isoforms of AKT were used to investigate the role of AKT in mutant K-ras-induced lung tumorigenesis in mice. Although deletion of Akt1 or Akt2 decreased NNK-induced lung tumor formation by 90%, deletion of Akt2 failed to decrease lung tumorigenesis in two other mouse models driven by mutant K-ras. Genetic mapping showed that Akt2 was tightly linked to the cytochrome P450 Cyp2a locus on chromosome 7. Consequently, targeted deletion of Akt2 created linkage to a strain-specific Cyp2a5 polymorphism that decreased activation of NNK in vitro. Mice with this Cyp2a5 polymorphism had decreased NNK-induced DNA adduct formation in vivo and decreased NNK-induced lung tumorigenesis. These studies support human epidemiological studies linking CYP2A polymorphisms with lung cancer risk in humans and highlight the need to confirm phenotypes of genetically engineered mice in multiple mouse strains. Published by Oxford University Press 2011.

AB - Lung tumors from smokers as well as lung tumors from mice exposed to tobacco carcinogens such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), often carry mutations in K-ras, which activates downstream-signaling pathways such as PI3K/AKT/mTOR pathway. Mice with genetic deletion of one of three isoforms of AKT were used to investigate the role of AKT in mutant K-ras-induced lung tumorigenesis in mice. Although deletion of Akt1 or Akt2 decreased NNK-induced lung tumor formation by 90%, deletion of Akt2 failed to decrease lung tumorigenesis in two other mouse models driven by mutant K-ras. Genetic mapping showed that Akt2 was tightly linked to the cytochrome P450 Cyp2a locus on chromosome 7. Consequently, targeted deletion of Akt2 created linkage to a strain-specific Cyp2a5 polymorphism that decreased activation of NNK in vitro. Mice with this Cyp2a5 polymorphism had decreased NNK-induced DNA adduct formation in vivo and decreased NNK-induced lung tumorigenesis. These studies support human epidemiological studies linking CYP2A polymorphisms with lung cancer risk in humans and highlight the need to confirm phenotypes of genetically engineered mice in multiple mouse strains. Published by Oxford University Press 2011.

UR - http://www.scopus.com/inward/record.url?scp=79961202687&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79961202687&partnerID=8YFLogxK

U2 - 10.1093/carcin/bgr097

DO - 10.1093/carcin/bgr097

M3 - Article

C2 - 21625009

AN - SCOPUS:79961202687

VL - 32

SP - 1279

EP - 1284

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 8

ER -