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J. Biol. Chem., Vol. 280, Issue 3, 2092-2104, January 21, 2005

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Genes Affecting the Cell Cycle, Growth, Maintenance, and Drug Sensitivity Are Preferentially Regulated by Anti-HER2 Antibody through Phosphatidylinositol 3-Kinase-AKT Signaling^*

Xiao-Feng Le, Amy Lammayot, David Gold, Yiling Lu¶, Weiqun Mao, Teresa Chang, Adarsh Patel, Gordon B. Mills¶, and Robert C. Bast, Jr.||

From the Departments of Experimental Therapeutics, Biostatistics, and ^¶Molecular Therapeutics, the University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

The molecular mechanisms by which the anti-HER2 antibodies trastuzumab and its murine equivalent 4D5 inhibit tumor growth and potentiate chemotherapy are not fully understood. Inhibition of signaling through the phosphatidylinositol 3-kinase (PI3K)-AKT pathway may be particularly important. Treatment of breast cancer cells that overexpress HER2 with trastuzumab inhibited HER2-HER3 association, decreased PDK1 activity, reduced Thr-308 and Ser-473 phosphorylation of AKT, and reduced AKT enzymatic activity. To place the role of PI3K-AKT in perspective, gene expression was studied by using Affymetrix microarrays and real time reverse transcription-PCR. Sixteen genes were consistently down-regulated 2.0–4.9-fold in two antibody-treated breast cancer cell lines. Fourteen of the 16 genes were involved in three major functional areas as follows: 7 in cell cycle regulation, particularly of the G₂-M; 5 in DNA repair/replication; and 2 in modifying chromatin structure. Of the 16 antibody-regulated genes, 64% had roles in cell growth/maintenance and 52% contributed to the cell cycle. Direct inhibition of PI3K with an inhibitor markedly reduced expression of 14 genes that were also affected by the antibody. Constitutive activation of AKT1 blocked the effect of the anti-HER2 antibody on cell cycle arrest and on eight differentially expressed genes. The antibody enhanced docetaxel-induced growth inhibition but did not increase the fraction of apoptotic cells induced with docetaxel alone. In contrast, the antibody plus docetaxel markedly down-regulated two genes, HEC and DEEPEST, required for passage through G₂-M. Thus, anti-HER2 antibody preferentially affects genes contributing to cell cycle progression and cell growth/maintenance, in part through the PI3K-AKT signaling. Transcriptional regulation by anti-HER2 antibody through PI3K-AKT pathway may potentiate the growth inhibitory activity of docetaxel by affecting cell cycle progression.

Received for publication, March 19, 2004 , and in revised form, October 21, 2004.

^* This work was supported in part by NCI Grant CA39930 from the National Institutes of Health (to R. C. B.) and by Grant 80094241 from the Goodwin Foundation (to X.-F. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 355, Houston, TX 77030-4009. Tel.: 713-792-7743; Fax: 713-792-7864; E-mail: rbast{at}mdanderson.org.

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