Simultaneous Suppression of Epidermal Growth Factor Receptor and c-erbB-2 Reverses Aneuploidy and Malignant Phenotype of a Human Ovarian Carcinoma Cell Line

Pack, Svetlana D.; Alper, Özgül M.; Stromberg, Kurt; Augustus, Meena; Özdemirli, Metin; Miermont, Anne M.; Klus, Greg; Rusin, Marek; Slack, Rebecca; Hacker, Neville F.; Ried, Thomas; Szállási, Zoltán; Alper, Özge

doi:10.1158/0008-5472.can-03-1982

Cited by 30 publications

(17 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ovarian cancer cells express EGF receptor, and EGF is an autocrine growth factor for ovarian cells (54,55). We have observed the absorption of EGF and MCP-1 by ovarian tumor cells in vitro incubated with serum, 6 indicating that lower circulating levels of these molecules in ovarian cancer patients might be due to the consumption by ovarian tumor expressing specific receptors (56,57).…”

Section: Discussionmentioning

confidence: 90%

Multiplexed Immunobead-Based Cytokine Profiling for Early Detection of Ovarian Cancer

Gorelik

Landsittel

Marrangoni

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

244

164

View full text Add to dashboard Cite

Early detection of ovarian cancer might improve clinical outcome. Some studies have shown the role of cytokines as a new group of tumor markers for ovarian cancer. We hypothesized that a panel comprised of multiple cytokines, which individually may not show strong correlation with the disease, might provide higher diagnostic power. To evaluate the diagnostic utility of cytokine panel, we used a novel multianalyte LabMAP profiling technology that allows simultaneous measurement of multiple markers. Concentrations of 24 cytokines (cytokines/chemokines, growth, and angiogenic factors) in combination with cancer antigen-125 (CA-125), were measured in sera of 44 patients with earlystage ovarian cancer, 45 healthy women, and 37 patients with benign pelvic tumors. Six markers, i.e., interleukin (IL)-6, IL-8, epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1), and CA-125, showed significant differences in serum concentrations between ovarian cancer and control groups. Out of this group, IL-6, IL-8, VEGF, EGF, and CA-125, were used in a classification tree analysis that resulted in 84% sensitivity at 95% specificity. The receiver operator characteristic curve created using the combination of markers produced sensitivities between 90% and 100% in the area of 80% to 90% specificity, whereas the receiver operator characteristic curve for CA-125 alone resulted in sensitivities of 70% to 80%. The classification tree analysis for discrimination of benign condition from ovarian cancer used CA-125, granulocyte colony-stimulating factor (G-CSF), IL-6, EGF, and VEGF resulting in 86.5% sensitivity and 93.0% specificity. The presented data show that simultaneous testing of a panel of serum cytokines and CA-125 using LabMAP technology may present a promising approach for ovarian cancer detection.

show abstract

Section: Discussionmentioning

confidence: 90%

Multiplexed Immunobead-Based Cytokine Profiling for Early Detection of Ovarian Cancer

Gorelik

Landsittel

Marrangoni

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

244

164

View full text Add to dashboard Cite

show abstract

“…We and others have demonstrated that gefitinib and trastuzumab have a synergistic anti-tumor effect in breast cancer cells that express both receptors. Synergism of anti-EGFR and anti-ErbB-2 agents has also been demonstrated in cells derived from tumors of different histological type, such as ovarian, non-small-cell lung and pancreatic carcinomas [28][29][30].…”

Section: Discussionmentioning

confidence: 94%

Effects of the combined blockade of EGFR and ErbB-2 on signal transduction and regulation of cell cycle regulatory proteins in breast cancer cells

D’Alessio

Luca

Maiello

et al. 2009

Breast Cancer Res Treat

View full text Add to dashboard Cite

International audienceTreatment of breast cancer cells with a combination of the EGFR-tyrosine kinase inhibitor (EGFR-TKI) gefitinib and the anti-ErbB-2 monoclonal antibody trastuzumab results in a synergistic antitumor effect. In this study, we addressed the mechanisms involved in this phenomenon. The activation of signaling pathways and the expression of cell cycle regulatory proteins were studied in SK-Br-3 and BT-474 breast cancer cells, following treatment with EGFR and/or ErbB-2 inhibitors. Treatment with the gefitinib/trastuzumab combination produced, as compared with a single agent, a more prolonged blockade of AKT and MAPK activation, a more pronounced accumulation of cells in the G0/G1 phase of the cell cycle, a more significant increase in the levels of p27 and of hypophosphorylated pRb2, and a decrease in the levels of Cyclin D1 and survivin. Similar findings were observed with the EGFR/ErbB-2 inhibitor lapatinib. Gefitinib, trastuzumab, and their combination increased the stability of p27, with the combination showing the highest effects. Blockade of both receptors with gefitinib/trastuzumab or lapatinib induced a significant increase in the levels of p27 mRNA and in the nuclear levels of the p27 transcription factor FKHRL-1. Inhibition of PI3K signaling also produced a significant raise in p27 mRNA. Finally, down-modulation of FKHRL-1 with siRNAs prevented the lapatinib-induced increase of p27 mRNA. The synergism deriving from EGFR and ErbB-2 blockade is mediated by several different alterations in the activation of signaling proteins and in the expression of cell cycle regulatory proteins, including transcriptional and posttranscriptional regulation of p27 expression

show abstract

“…Nonetheless, erbB2 receptor does not act in isolation. Although simultaneous suppression of EGFR and erbB2 results in a less malignant phenotype in ovarian cancer cells (Pack et al, 2004), only a minority of erbB2 altered breast cancers have co-existent overexpression of EGFR. Most metastatic breast cancers show expression for either EGFR or erbB2, and less often for both (Grupka et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Elevated expression of erbB3 confers paclitaxel resistance in erbB2-overexpressing breast cancer cells via upregulation of Survivin

et al. 2010

View full text Add to dashboard Cite

The coexpression of erbB3 and erbB2 is frequently observed in breast cancer; and erbB3 has a critical role in erbB2 promotion of breast cancer progression and anti-estrogen resistance. In this study, we determine the role of erbB3 in erbB2-mediated paclitaxel resistance in breast cancer cells. The overexpression of exogenous erbB3 via either stable or transient transfection in erbB2-overexpressing, but not epidermal growth factor receptor (EGFR)-expressing, breast cancer cells significantly decreases paclitaxel-induced growth inhibition and apoptosis. Consistently, knockdown of erbB3 expression with a specific short hairpin RNA (shRNA) in breast cancer cells with coexpression of both erbB2 and erbB3 enhances paclitaxel-induced apoptosis evidenced by increased DNA fragmentation, poly (ADP-ribose) polymerase (PARP) cleavage and activation of caspase-3 and -8. Furthermore, while forced overexpression of erbB3 increases, specific knockdown of erbB3 decreases the expression levels of Survivin only in the erbB2-overexpressing breast cancer cells. Targeting Survivin with specific shRNA overcomes paclitaxel resistance without effect on the expression levels of either erbB2 or erbB3. Mechanistic studies indicate that the specific phosphoinositide 3-kinase (PI-3K), Akt and mammalian target of rapamycin (mTOR) inhibitors, but not the mitogen-activated protein kinase kinase (MEK) inhibitor, not only abrogate erbB3-mediated upregulation of Survivin, but also reinforce the erbB2/erbB3-coexpressing breast cancer cells to paclitaxel-induced growth inhibition. These data demonstrate that heterodimerization of erbB2/erbB3 is a prerequisite for erbB2 tyrosine kinase activation; and elevated expression of erbB3 is required for erbB2-mediated paclitaxel resistance in breast cancer cells via PI-3K/Akt/ mTOR signaling pathway-dependent upregulation of Survivin. Our studies suggest that new strategies targeting erbB3 or Survivin may enhance the efficacy of chemotherapeutic agents against erbB2-overexpressing breast cancer.

show abstract

Simultaneous Suppression of Epidermal Growth Factor Receptor and c-erbB-2 Reverses Aneuploidy and Malignant Phenotype of a Human Ovarian Carcinoma Cell Line

Cited by 30 publications

References 19 publications

Multiplexed Immunobead-Based Cytokine Profiling for Early Detection of Ovarian Cancer

Multiplexed Immunobead-Based Cytokine Profiling for Early Detection of Ovarian Cancer

Effects of the combined blockade of EGFR and ErbB-2 on signal transduction and regulation of cell cycle regulatory proteins in breast cancer cells

Elevated expression of erbB3 confers paclitaxel resistance in erbB2-overexpressing breast cancer cells via upregulation of Survivin

Contact Info

Product

Resources

About