Abstract
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 G(2)-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 G(2)-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.
Highlights
The human epidermal growth factor receptor 2 (HER2,1 known as c-Neu or ErbB-2) encodes a 185-kDa transmembrane
We have extended these studies to determine the mechanisms by which anti-HER2 antibody mediates these actions by investigating the effect of anti-HER2 antibody on HER2-HER3 association, phosphoinositide-dependent kinase-1 (PDK1) kinase activity, phosphorylation of AKT at threonine 308 (Thr-308 AKT), and AKT enzymatic activity
As demonstrated previously [23, 24], the signaling from HER2 to phosphatidylinositol 3-kinase (PI3K)-AKT pathway depends on the formation of HER2-HER3 heterodimers because HER3 has multiple consensus binding sites for the p85 PI3K subunit
Summary
The human epidermal growth factor receptor 2 (HER2,1 known as c-Neu or ErbB-2) encodes a 185-kDa transmembrane. We have further shown that posttranslational regulation of p27Kip plays a critical role in the anti-HER2 antibody-mediated G1 cell cycle arrest and tumor growth inhibition [12]. Anti-HER2 antibodies that inhibit tumor growth prevent HER2-HER3 interaction and inhibit the PI3K-AKT signaling pathway [6, 11, 16, 17]. Treatment with anti-HER2 antibody decreased the expression of 16 genes Fourteen of these 16 genes contribute to the following three different areas of cell function: cell cycle regulation, DNA repair/replication, and modification of chromatin structure. Direct inhibition of PI3K markedly decreased the expression of 14 genes regulated by the anti-HER2 antibody. A combination of anti-HER2 antibody and docetaxel exerted additive growth inhibition against breast cancer cell lines that overexpressed HER2. The combination did not increase the fraction of apoptotic cells induced with docetaxel alone but markedly down-regulated two genes that participate in cell cycle regulation, HEC and DEEPEST, required for passage through G2-M
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