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Carcinogenesis Advance Access originally published online on July 7, 2004
Carcinogenesis 2004 25(11):2053-2059; doi:10.1093/carcin/bgh226
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Carcinogenesis vol.25 no.11 © Oxford University Press 2004; all rights reserved.

ARTICLE

Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions

Binaifer R. Balsara1,*, Jianming Pei1,*, Yasuhiro Mitsuuchi1, Robert Page2, Andres Klein-Szanto2, Hao Wang3, Michael Unger4 and Joseph R. Testa1,5

1 Cancer Genetics, 2 Tumor Cell Biology, 3 Biostatistics and 4 Pulmonary Cancer Detection and Prevention Programs, Fox Chase Cancer Center, Philadelphia, PA 19111, USA

5 To whom correspondence should be addressed. Tel: +1 215 728 2610; Fax: +1 215 214 1623; Email: joseph.testa{at}fccc.edu

AKT is frequently activated in various cancers, but its involvement in lung tumor development and progression is not well established. We examined AKT activity by immunohistochemistry in 110 non-small cell lung carcinomas (NSCLCs) using tissue microarrays. AKT activation was observed in 56 (51%) tumors. To further validate activation of the AKT pathway in this series, we examined the phosphorylation status of the mammalian target of rapamycin (mTOR) and forkhead (FKHR), two downstream targets of AKT. Positive staining for phospho-mTOR and phospho-FKHR were detected in 74% and 68% of tumors, respectively, and was significantly associated with activation of AKT. Tumors positive for phosphorylated (active) AKT were present with a similar frequency in low stage (I/II) and high stage (III/IV) tumors, raising the possibility that AKT activation occurs early in tumor progression. We therefore examined AKT activity in 25 bronchial epithelial lesions from 12 patients at high risk of lung cancer. Metaplastic/dysplastic areas showed AKT activity, whereas normal and hyperplastic bronchial epithelia exhibited little or no activity. Since some bronchial epithelial lesions may develop into invasive cancers, we examined the effect of AKT on invasiveness of lung cancer cells, using an in vitro cell invasion assay. Transfection of NSCLC cells with wild-type AKT increased invasiveness in response to hepatocyte growth factor, whereas transfection with dominant negative AKT abrogated this effect. Collectively, these data suggest that AKT activation is a frequent and early event in lung tumorigenesis, which may enhance risk of progression to malignancy. Thus, AKT represents a potentially important target for chemoprevention in individuals at high risk of NSCLC.


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