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Published ahead of print on August 18, 2004, doi:10.1164/rccm.200404-487OC

Am. J. Respir. Crit. Care Med., Volume 170, Number 10, November 2004, 1088-1094

A more recent version of this article appeared on November 15, 2004
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Submitted on April 14, 2004
Accepted on August 18, 2004

Early Involvement of the Phosphatidylinositol 3-kinase/Akt Pathway in Lung Cancer Progression

Pierre P Massion1*, Peter M Taflan2, Yu Shyr3, S M Jamshedur Rahman2, Pinar Yildiz2, Bashar Shakthour3, Mary E Edgerton4, Matthew Ninan5, Jeremiah J Andersen6, and Adriana L Gonzalez6

1 Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University, Nashville, TN, USA; Medical Service, Nashville Veterans Affairs Medical Center, Nashville, TN, USA, 2 Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University, Nashville, TN, USA, 3 Department of Medicine, Biostatistics Shared Resource, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University, Nashville, TN, USA, 4 Tissue Informatics Shared Resource, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University, Nashville, TN, USA; Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN, USA, 5 Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA, 6 Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN, USA

* To whom correspondence should be addressed. E-mail: pierre.massion{at}mcmail.vanderbilt.edu.

Signaling through the phosphatidylinositol 3-kinase pathway has been associated with lung tumorigenesis. We examined the association between gene copy number of the phosphatidylinositol 3-kinase catalytic subunit {alpha} and phosphorylated Akt expression in invasive and preinvasive lung cancers. We sought to determine at what stage of tumor development gene copy number increase or phosphorylated Akt overexpression might affect tumor development. We assessed phosphatidylinositol 3-kinase catalytic subunit {alpha} gene copy number by fluorescence in situ hybridization and phosphorylated Akt expression by immunohistochemistry in 242 invasive and 43 preinvasive lung cancers and correlated our findings with clinical outcome. The phosphatidylinositol 3-kinase gene catalytic subunit {alpha} was amplified in 70% of squamous carcinomas, 38% of large cell carcinomas, 19% of adenocarcinomas, and 67% of small cell lung cancers. Phosphorylated Akt overexpression was frequently observed and strongly so in 12-17% of lung cancers depending on nuclear or cytoplasmic localization. Neither phosphatidylinositol 3-kinase catalytic subunit {alpha} gene copy number nor phosphorylated Akt expression had prognostic significance. In preinvasive lesions, amplification of the phosphatidylinositol 3-kinase gene catalytic subunit {alpha} and overexpression of phosphorylated Akt were associated with severe dysplasia and each other. These observations suggest frequent and early involvement of the phosphatidylinositol 3-kinase pathway in lung cancer.
Key words: tumorigenesis, amplification, preinvasive, PKB, tissue microarray




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