Carcinogenesis Advance Access published online on August 1, 2003
Carcinogenesis, doi:10.1093/carcin/bgg125
© 2003 by Oxford University Press
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CANCER BIOLOGY
1 Basic Research Program, SAIC Frederick, National Cancer Institute at Frederick, Frederick MD 21702-1201, USA
* Corresponding author. E-mail: sithanan{at}mail.ncifcrf.gov.
Received 20 March 2003
; revised 17 June 2003
; accepted 16 July 2003
Although ErbB3, a member of the epidermal growth factor receptor family, has been implicated in mammary tumorigenesis, investigation of its role in lung tumorigenesis has been limited. We found that ErbB3 was present at high levels in five of seven human lung adenocarcinoma cell lines examined, along with its ligands, heregulins
lung adenocarcinoma, ErbB3, PI3 kinase, Akt, cell cycle
Cell cycle activation in lung adenocarcinoma cells by the ErbB3/phosphatidylinositol 3 kinase/Akt pathway
2 Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick MD 21702-1201, USA
3 Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan, 464-8681
and 
, whereas ErbB3 was absent from HPL1D, a nontransformed cell line from human pulmonary peripheral epithelium. Interactions and effects of ErbB3 were studied in detail in adenocarcinoma lines H441 and H1373. Complexes containing phosphorylated ErbB2, phosphorylated ErbB3, and the p85 regulatory subunit of phosphoinositidyl 3 kinase were detected by co-immunoprecipitation experiments and were present constitutively even in the absence of serum-stimulated cell division. Serum treatment increased the pErbB3/p85 complexes and also stimulated phosphorylation of Akt and GSK3, increase in cyclin D1, and cell cycle progression, and these events were blocked by the Akt activation inhibitor LY294002. An ErbB3-specific antisense oligonucleotide reduced amounts of ErbB3 protein and p85 complex in both cell lines, and significantly suppressed cell proliferation. These results together suggest involvement of ErbB3 in growth of lung adenocarcinomas, through activation of phosphoinositidyl 3 kinase and Akt, inactivation of GSK3, and stabilization of cyclin D1 for cell cycle maintenance. It could be a useful therapeutic target.
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