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. 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. The human epidermal growth factor receptor 2 (HER2, 1The abbreviations used are: HER2, human epidermal growth factor receptor 2; PI3K, phosphatidylinositol 3-kinase; RT, reverse transcription; PCNA, proliferating cell nuclear antigen; FC, fold change; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MES, 4-morpholineethanesulfonic acid; PBS, phosphate-buffered saline; hIgG, human IgG; m, mammalian. 1The abbreviations used are: HER2, human epidermal growth factor receptor 2; PI3K, phosphatidylinositol 3-kinase; RT, reverse transcription; PCNA, proliferating cell nuclear antigen; FC, fold change; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MES, 4-morpholineethanesulfonic acid; PBS, phosphate-buffered saline; hIgG, human IgG; m, mammalian. also known as c-Neu or ErbB-2) encodes a 185-kDa transmembrane tyrosine kinase growth factor receptor. The ligand that binds to the homodimers of HER2 has not yet been identified. Rather, HER2 functions as a preferred co-receptor to form heterodimers with HER1 (epidermal growth factor receptor), HER3, or HER4. Of these heterodimers, HER2-HER3 is particularly important for intracellular signaling (1Citri A. Skaria K.B. Yarden Y. Exp. Cell Res. 2003; 284: 54-65Crossref PubMed Scopus (475) Google Scholar). HER2 signaling has been linked to a variety of cellular responses to growth factors under both normal and pathophysiological conditions. HER2 signaling is required not only during normal development of the mammary gland but also during development of the glia, neurons, and heart (1Citri A. Skaria K.B. Yarden Y. Exp. Cell Res. 2003; 284: 54-65Crossref PubMed Scopus (475) Google Scholar, 2Stern D.F. Exp. Cell Res. 2003; 284: 89-98Crossref PubMed Scopus (107) Google Scholar). Amplification of the HER2 gene and overexpression of HER2 protein have been documented in ∼30% of breast and 15% of ovarian cancers (3Pegram M.D. Konecny G. Slamon D.J. Cancer Treat. Res. 2000; 103: 57-75Crossref PubMed Scopus (174) Google Scholar). In many (but not all) reports, HER2 overexpression has been associated with a more aggressive course of disease. Although the underlying mechanisms for this association are still not well characterized, HER2 overexpression has been linked to increased proliferation and invasiveness (4Holbro T. Civenni G. Hynes N.E. Exp. Cell Res. 2003; 284: 99-110Crossref PubMed Scopus (519) Google Scholar). HER2 is currently one of the best defined targets for specific therapy. The substantially greater expression of HER2 on cancer cells than on normal epithelial tissues permits selective targeting of malignant cells. HER2 is expressed on the cell surface where it can interact with ligands and antibodies (1Citri A. Skaria K.B. Yarden Y. Exp. Cell Res. 2003; 284: 54-65Crossref PubMed Scopus (475) Google Scholar, 2Stern D.F. Exp. Cell Res. 2003; 284: 89-98Crossref PubMed Scopus (107) Google Scholar, 3Pegram M.D. Konecny G. Slamon D.J. Cancer Treat. Res. 2000; 103: 57-75Crossref PubMed Scopus (174) Google Scholar, 4Holbro T. Civenni G. Hynes N.E. Exp. Cell Res. 2003; 284: 99-110Crossref PubMed Scopus (519) Google Scholar). Trastuzumab, a monoclonal antibody directed against the extracellular domain of HER2, is therapeutically active in HER2-positive breast carcinomas (3Pegram M.D. Konecny G. Slamon D.J. Cancer Treat. Res. 2000; 103: 57-75Crossref PubMed Scopus (174) Google Scholar). Clinical trials in HER2-positive patients with breast cancer have demonstrated that targeted therapy with trastuzumab in with chemotherapy as and time to progression and (3Pegram M.D. Konecny G. Slamon D.J. Cancer Treat. Res. 2000; 103: 57-75Crossref PubMed Scopus (174) Google Scholar, Cancer Res. 2003; PubMed Scopus Google Scholar). Clinical trials have also documented an increased for trastuzumab is with that HER2 signaling may to normal heart The mechanisms by which trastuzumab affects growth of HER2-positive cancer cells and to chemotherapy are not fully understood. antibody can the HER2 receptor and of the extracellular domain of the receptor PubMed Google Scholar). a of and of anti-HER2 antibody can also intracellular signaling by kinase activity and and have demonstrated that anti-HER2 monoclonal antibodies inhibitory on breast cancer cells through of cell cycle arrest associated with of and of A. Cancer Res. 2000; Google Scholar, Hynes N.E. 2000; PubMed Scopus Google Scholar, Slamon D.J. Cancer Res. Google Scholar, Google Scholar, Hynes N.E. 2000; PubMed Scopus Google Scholar, Cancer Res. Google Scholar). have that regulation of a role in the anti-HER2 cell cycle arrest and tumor growth inhibition A. 2003; Scholar). Of the have that of the phosphorylation of protein is the by which anti-HER2 antibody the protein A. 2003; Scholar). antibodies that inhibit tumor growth also HER2-HER3 and inhibit the PI3K-AKT signaling pathway A. Cancer Res. 2000; Google Scholar, Cancer Res. Google Scholar, A. Cancer Res. 2000; Google Scholar, PubMed Scopus Google Scholar). the PI3K-AKT pathway is important to cell inhibition of the PI3K-AKT pathway may in the of trastuzumab to G. Cancer Res. Google Scholar). also DNA M.D. Slamon D.J. PubMed Scopus Google through as yet contributing to the of the antibody to the effect of as M.D. Slamon D.J. PubMed Scopus Google and Res. Scopus Google Scholar). In trastuzumab and cellular PubMed Google Scholar, A. Y. Cancer Res. Google contributing to its activity. or of the receptor on has been to the effect of trastuzumab in 2000; PubMed Scopus Google of Of the mechanisms for the of anti-HER2 of the PI3K-AKT pathway may be for to docetaxel and the mechanisms of of the anti-HER2 antibody and the of the antibody on activation of AKT as well as on to antibody inhibited HER2-HER3 association, decreased PDK1 activity, reduced Thr-308 phosphorylation of AKT, and reduced AKT enzymatic activity. have used a to the that with anti-HER2 antibody and with the inhibitor of Treatment with anti-HER2 antibody decreased the expression of 16 genes. Fourteen of these 16 genes to the three areas of cell cell cycle regulation, DNA and of chromatin structure. Direct inhibition of PI3K markedly decreased the expression of 14 genes by the anti-HER2 antibody. active AKT cell cycle arrest and of cell cycle genes induced by anti-HER2 antibody. of anti-HER2 antibody and docetaxel growth inhibition against breast cancer cell that The did not increase the fraction of apoptotic cells induced with docetaxel but markedly down-regulated two genes that in cell cycle regulation, HEC and DEEPEST, required for passage through G2-M. Cell human breast cancer cell and were the cells were in that with 2 of and in with cells were in with 2 and cells were with cell cells were or in in cells were with anti-HER2 antibody 4D5 or trastuzumab in for or antibody as antibody for 4D5 and was used in cells. as antibody for trastuzumab and was used in cells. murine monoclonal antibody 4D5 and monoclonal antibody trastuzumab were by murine cells were the cells were in the of to and the was as 2000; PubMed Scopus Google Scholar). was and against to with AKT, AKT, and AKT as well as an AKT kinase were Cell monoclonal antibody to was antibody to AKT1 and a PDK1 kinase were antibody with HER2 was antibody to and was monoclonal antibody to was human was Affymetrix that of the expression of human genes were Affymetrix of cells were with 4D5 or for cells were with trastuzumab or for was the or cells using the were to the The of was by and of the of of were and by of and on were the of were used for Affymetrix and of for Affymetrix of of were used in the with by The was 16 by DNA DNA and the was by the of DNA to the of was by with The was used as in an in to with using the The was to the and was with a of was by in a and for was the of and the of to the of the were used for Affymetrix and to the human was the Cancer by using an Affymetrix The was with Affymetrix for 16 were in a with is plus of and for and with MES, and for and with was by with antibody. The were in an to was was for and by of the gene on the To the of the and of the Affymetrix were using and the the were are the The by were and to of for of Affymetrix the Affymetrix Affymetrix the and the of and was by using the of and cells on the of The of and were as a of to that had been was by the of by Affymetrix for a was expressed a to be on the a are than of are the is not one a the for cell of and The in was to on the were for were used to gene Affymetrix was used for to fold on the a for on the a for used to the or for and a for or expression The Affymetrix were not a was differentially expressed the was the in one was and the of the to a the was by the of M.D. Cancer PubMed Scopus Google Scholar). The the on a DNA and a is used to the of is for in has been 2003; PubMed Scopus Google Scholar). 2003; PubMed Scopus Google using as for expression two a and The were to in cell a of gene expression was and cell lines. The of with Affymetrix the with and The are of in The of with the and The for the were to Although have used to a as the for the differentially expressed genes in this the Affymetrix was with a or of of the was used as a for genes and in that the and for real time were in this with of the used in this are as follows: protein and and and and To the and to a that two genes, one and one gene of or in the was was in of of for and of and using of The were by or of or and or The was for the of the cycle. The was by were to and were to expression of the using were by two and in both and cell lines. cycle were used for and and and To or a and a were in expression of genes that are induced by anti-HER2 expression of anti-HER2 antibody-treated antibody-treated in gene protein kinase protein and cell nuclear and factor and kinase kinase expressed in expression of anti-HER2 antibody-treated antibody-treated in in a gene expression real time was with an using to the for the 14 genes in for which are The and for HEC and were gene expression gene was used as The were by using and the was with a the and the were linked the of as The were as follows: for by for of for by for were in Amplification were with an To the expression of the genes of to the were for gene and the in the of the gene and the of were which was by the than of the of the by the was used to the expression the of the gene and the of were not the expression of Res. Scopus Google which the effect of was used to the expression of of Cell and were as A. Cancer Res. 2000; Google Scholar). was as PubMed Scopus Google Scholar). or cells were on using The were and with for were in and with in for to activity. of antibodies was blocked by with for and were with the monoclonal antibody of for 2 The were three with PBS, for with and by in for the the were with and with of AKT1 and human AKT1 with an was by using the and cells. The was The AKT1 was expression The human AKT1 and in were by DNA cells were with the expression or by using as by the Cell cell growth in a was used to the growth as M.D. Slamon D.J. PubMed Scopus Google Scholar). Cell was as A. Cancer Res. 2000; Google Scholar). was used to with were PI3K-AKT a A. Cancer Res. 2000; Google demonstrated that with anti-HER2 antibody decreased PI3K activity and reduced phosphorylation of AKT on Ser-473 In this have these to the mechanisms by which anti-HER2 antibody these by the effect of anti-HER2 antibody on HER2-HER3 association, kinase activity, phosphorylation of AKT and AKT enzymatic activity. demonstrated PubMed Scopus Google Scholar, T. Hynes N.E. A. 2003; PubMed Scopus Google the signaling HER2 to PI3K-AKT pathway on the of HER2-HER3 heterodimers has for the PI3K To association of HER2 and HER3, were with the anti-HER2 antibody A. Cancer Res. 2000; Google and were with anti-HER2 and Treatment of cells with 4D5 decreased the association of HER2 and by with the association was enhanced by under with the ligand PDK1 which is to the by the of PI3K, is an of PI3K and is for the phosphorylation of Thr-308 on AKT 2000; PubMed Scopus Google Scholar). The PDK1 enzymatic activity was inhibited by trastuzumab in a with A. Cancer Res. 2000; Google phosphorylation of Ser-473 AKT was down-regulated by 4D5 or trastuzumab in both and cells and in and phosphorylation of Thr-308 AKT was also down-regulated by 4D5 or trastuzumab in and in both and cell lines. activity of AKT was also inhibited by trastuzumab in a Thus, anti-HER2 antibodies inhibited cellular signaling through the PI3K-AKT Treatment with in of the Cell Cell Cell and the by which inhibition of PI3K signaling to the of anti-HER2 have the of anti-HER2 antibody and of PI3K inhibition on gene expression by and breast cancer cells that overexpress were with anti-HER2 antibody or or antibody or was to of for Affymetrix The gene was used to expression of known human genes. as under and on the two of anti-HER2 antibody down-regulated expression of genes in and genes in Treatment with anti-HER2 antibody expression of genes in and 16 genes in cells. in both cell were genes were down-regulated and genes were to these that more be required to genes were that a to a in both cell 16 genes were and genes were real time or the expression of 16 genes. Thus, anti-HER2 antibody a inhibitory effect on gene expression in breast cancer cells that the 16 differentially expressed genes, had been and one gene had not been Of the known genes, 14 three functional areas as follows: cell cycle regulation, DNA and chromatin the of Affymetrix functional have the fraction of differentially expressed genes in of functional to the fraction in for of the genes on the Of the 16 antibody-regulated genes, 64% had roles in cell growth/maintenance and 52% contributed to cell cycle progression. the only 5 and of genes to cell growth/maintenance and to the cell The that the genes involved in cell cycle and cell growth/maintenance were preferentially by anti-HER2 antibody. in the of the Cell genes DEEPEST, and that to cell cycle were down-regulated by by anti-HER2 antibody of these cell cycle genes is that in the which to the activity and anti-HER2 antibody. To these cell cycle genes were down-regulated by anti-HER2 antibody real time and were as under and cells were with 4D5 or antibody for of in genes were down-regulated by anti-HER2 antibody in a as by real time with the Affymetrix genes were down-regulated the of 4D5 in cells To these gene expression cells were with trastuzumab or antibody for of to the inhibition of genes was by real time in cells The of expression was also by to trastuzumab in cells and expression was also inhibited by 4D5 in cells not The of a specific antibody of the of the protein by as in Thus, anti-HER2 antibody cell cycle genes that particularly on the cell cycle in of DNA and genes and involved in of DNA and were down-regulated by anti-HER2 antibody was not only by real time but also protein by and in both and cell lines. The in was more in cells than that in cells The in expression of protein was more than that of in cells The anti-HER2 genes that in DNA and and were also by real time in both cells and cells of and expression by the antibodies was and were down-regulated by more than by the antibody The of of was inhibition of expression was more Thus, anti-HER2 antibody is to genes involved in DNA and of DNA and genes. The DNA and genes and were by real time as under and in cells and in cells to the to the two genes and that chromatin and gene were down-regulated by the anti-HER2 antibody. in and real time in and the of these two genes in both and and and cell with the anti-HER2 for the that genes are one of the targets of the anti-HER2 antibody. Direct PI3K Inhibition by the with anti-HER2 antibody cancer cell signaling through and genes that cell DNA and chromatin structure. To the that genes down-regulated by with anti-HER2 antibody are by PI3K breast cancer cells that overexpress HER2 were with of PI3K to or not the genes down-regulated by the antibody are down-regulated by inhibition of time and and were to the of PI3K in inhibition of PI3K with expression of cell genes and in a as demonstrated by real time the activity of the anti-HER2 antibody in cell gene was also inhibited by DNA and genes PCNA, and were by as by real time also reduced the expression of two chromatin genes and as demonstrated by real time and that and anti-HER2 antibody to on the 14 differentially expressed genes, with the that PI3K signaling of the of anti-HER2 antibody. Constitutive of AKT1 the of to and to Cell signaling through the PI3K particularly the PI3K-AKT of the genes, expression of a AKT the to anti-HER2 a expression for AKT1 and it cells. in the expressed a of AKT1 protein that was active as by phosphorylation of both Ser-473 and The of anti-HER2 antibody on the differentially expressed genes and cell cycle were in two active The expression of active blocked the of and genes of and genes and and of and genes and induced by the anti-HER2 antibody. active did not the of DEEPEST, and PCNA, and by the anti-HER2 antibody. antibody did the expression of these 14 genes in the that the not expression of active the cell cycle progression by cells in the with the of active decreased to or to in the two anti-HER2 cell cycle these that the differentially expressed genes in by PI3K-AKT and inhibition of the PI3K-AKT pathway is an important for the activity of anti-HER2 antibody. Inhibition with of HEC and antibody was to the of in and (3Pegram M.D. Konecny G. Slamon D.J. Cancer Treat. Res. 2000; 103: 57-75Crossref PubMed Scopus (174) Google Scholar, M.D. Slamon D.J. PubMed Scopus Google Scholar). and are that and and arrest cell in 2003; PubMed Scopus Google Scholar). Treatment of breast cancer cells with anti-HER2 antibodies reduced expression of the genes that particularly in the of the cell cycle 2 and to the of with anti-HER2 antibody and docetaxel on these cell cycle genes in this Inhibition of cell growth of cells with a of 4D5 anti-HER2 antibody and docetaxel was using a A. 2003; Scholar, M.D. Slamon D.J. PubMed Scopus Google Scholar). in docetaxel inhibited cell growth by anti-HER2 antibody 4D5 inhibited growth by of 4D5 and docetaxel greater inhibition of antibody and docetaxel growth inhibition the of 4D5 and docetaxel did not more apoptotic cells than did and docetaxel with the plus more cells in the and cells in the in with 4D5 and docetaxel that the effect of anti-HER2 antibody on cell cycle regulation to its to potentiate the growth inhibition of the expression of cell genes was a of 4D5 antibody and docetaxel down-regulated the expression of HEC real time and docetaxel and antibody plus docetaxel did not or increased the expression of HEC and and The cell cycle genes that were by anti-HER2 antibody and were not down-regulated by with a of 4D5 and docetaxel not Thus, enhanced of HEC and expression by anti-HER2 antibody and docetaxel was associated with greater inhibition of tumor growth in breast cancer cells that overexpress Treatment of breast cancer cells that overexpress with anti-HER2 antibody inhibited HER2-HER3 association, decreased PDK1 activity, reduced Thr-308 and Ser-473 phosphorylation of AKT, and reduced AKT enzymatic activity. signaling through AKT with the of HER2-HER3 heterodimers, phosphorylation of and of PI3K was for the extracellular domain of HER2 with trastuzumab A. PubMed Scopus Google Scholar). binds to domain of the receptor on the of the of HER2 a the for an domain that of A. PubMed Scopus Google Scholar). Thus, anti-HER2 antibodies 4D5 and trastuzumab the HER2-HER3 activation of the PI3K-AKT in this and that anti-HER2 antibodies inhibit PI3K-AKT signaling Cancer Res. Google Scholar, A. Cancer Res. 2000; Google Scholar, PubMed Scopus Google Scholar). To the of of anti-HER2 gene expression in breast cancer cells with anti-HER2 antibody was with that in cells with antibody. Sixteen genes were down-regulated by anti-HER2 with known and not yet Fourteen of the known genes were the three major functional 7 in cell cycle regulation to the 5 in DNA repair/replication; and 2 affecting chromatin antibody had the on genes affecting cell cycle and cell growth/maintenance gene was down-regulated by anti-HER2 antibody. may expression PubMed Scopus Google but decreased expression with anti-HER2 antibody that regulation of this gene not to growth of trastuzumab and growth of human breast cancer cell M.D. Slamon D.J. PubMed Scopus Google Scholar). Treatment of human breast cancer using a of trastuzumab and of tumor with of with Cancer Res. Google Scholar). Clinical have demonstrated substantially greater trastuzumab and are used to patients with breast cancers that overexpress HER2 D.J. A. T. PubMed Scopus Google Scholar). The mechanisms underlying the and trastuzumab of by anti-HER2 antibody has been as an important underlying growth inhibition G. Cancer Res. Google Scholar). The of docetaxel and trastuzumab has also been to be active against breast cancers that overexpress HER2 PubMed Scopus Google Scholar). with anti-HER2 antibody did not docetaxel-induced Rather, the of anti-HER2 antibody increased growth inhibition a increase in the fraction of apoptotic cells. growth inhibition was associated with enhanced of two genes involved in the of the cell HEC and Although trastuzumab may increase in cell G. Cancer Res. Google that inhibition of expression of cell cycle genes by anti-HER2 antibody also may to the molecular mechanisms by which anti-HER2 antibody the activity of can also DNA M.D. Slamon D.J. PubMed Scopus Google contributing to the of the effect of and of the DNA genes, a in DNA is to the HER2 the and is or in of breast A. PubMed Scopus (174) Google Scholar). expression was down-regulated by anti-HER2 antibody on Affymetrix and decreased gene expression was in both cell by real time activity, with anti-HER2 antibody also the to as Y. Cancer 2003; Google have that trastuzumab of breast cancer cell that overexpress HER2 through the PI3K-AKT in and 7 demonstrated that trastuzumab down-regulated genes that to DNA PCNA, and through the PI3K this one by which trastuzumab can potentiate the of and on breast cancer cells that overexpress The effect of anti-HER2 antibody on genes associated with regulation of chromatin is a that mechanisms of for anti-HER2 antibody. and are that are to DNA DNA and to PubMed Scopus Google Scholar, PubMed Google Scholar). in of breast cancer cells of and and associated with the HER2 A. PubMed Scopus Google Scholar). of as and can of HER2 Cancer Google Scholar). kinase associated with chromatin can be as a of HER2 signaling A. A. PubMed Scopus Google Scholar). it is that anti-HER2 antibody gene expression and activity through of The of anti-HER2 antibody and inhibition of PI3K to a of genes that anti-HER2 antibody its in through inhibition of signaling through the PI3K-AKT is by the that AKT can the of anti-HER2 antibody on the expression of a of genes. Although the PI3K-AKT pathway is associated with progression and cell a of have the PI3K-AKT signaling in regulation of the as well A. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, A. PubMed Scopus Google Scholar). which demonstrated that PI3K inhibitor the expression of genes DEEPEST, and the role of PI3K-AKT in the that the PI3K-AKT may be involved in a greater of cellular functions than of active blocked anti-HER2 inhibition of eight genes but did not expression of the genes that the pathway is not the only signaling pathway involved in regulation of the cell cycle and DNA chromatin genes, and may be through the PI3K-AKT on the in and AKT PI3K as and may also be involved in the regulation of these genes and in the mechanisms of for the antibody. and that trastuzumab has a effect on and as the cells were to with anti-HER2 antibody that PI3K-AKT is a pathway but not the only pathway that the mechanisms of for the antibody. have anti-HER2 antibody breast cancer cells the of the cell cycle and the of cells the A. Cancer Res. 2000; Google Scholar, A. 2003; Scholar). that anti-HER2 antibody markedly the expression of genes DEEPEST, and that this of the genes cell cycle In of the role of PI3K-AKT in cell cycle it is also that anti-HER2 antibody may have on both and which to arrest and of cell cycle and to inhibition of proliferation of breast cancer cells. The to the by which anti-HER2 antibody proliferation and in with docetaxel to tumor antibody affects the genes involved in cell cycle particularly in the DNA and and chromatin demonstrated that inhibition of PI3K-AKT signaling is an important by which the anti-HER2 antibody cell cycle arrest and a of genes. that the of growth inhibition with the of anti-HER2 antibody and docetaxel is associated with enhanced of two genes, HEC and for the PDK1 and and for Affymetrix Affymetrix and were the which is in part by the Cancer also the also by for with
No takes yet. Share an insight, caveat, or question.
Le et al. (2004) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: