Overexpression of ErbB2 in cancer and ErbB2-targeting strategies

Yu, Dihua; Hung, Mien‐Chie

doi:10.1038/sj.onc.1203972

Cited by 369 publications

(320 citation statements)

References 66 publications

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“…HER2 is amplified and/or overexpressed in about 20-30% of cases of human breast cancer. HER2 overexpression correlates with large tumor size, tumor spread to lymph nodes, high grade, high percentage of S phase cells, aneuploidy, higher metastatic potential, and decreased survival, all consistent with an increase in the growth and metastatic potential of cancer cells (Yu and Hung, 2000). Blocking HER2 signaling arrests cancer cells in the G1 phase of the cell cycle and inhibits the growth of xenografts of tumors that overexpress HER2.…”

Section: Introductionmentioning

confidence: 69%

HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

et al. 2006

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We determined the impact of HER2 signaling on two proangiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), and on an antiangiogenic factor, thrombospondin-1 (TSP-1). Re-expression of HER2 in MCF-7 and T-47D breast cancer cells that endogenously express low levels of HER2 resulted in elevated expression of VEGF and IL-8 and decreased expression of TSP-1. Inhibition of HER2 with a humanized anti-HER2 antibody (trastuzumab, or Herceptin s ) or a retrovirus-mediated small interfering RNA against HER2 (siHER2) decreased VEGF and IL-8 expression, but increased TSP-1 expression in BT474 breast cancer cells that express high levels of HER2. These in vitro results were further evaluated by treatment of BT474 xenografts in immunosuppressed mice with trastuzumab. Trastuzumab inhibited growth of BT474 xenografts and decreased microvascular density associated with downregulation of VEGF and IL-8 and with upregulation of TSP-1 expression. Inhibiting the PI3K-AKT pathway decreased VEGF and IL-8 expression. AKT1 overexpession increased VEGF and IL-8 expression, but did not increase TSP-1 expression. A p38 kinase inhibitor, SB203580, instead blocked TSP-1 expression and a p38 activator, MKK6, increased TSP-1 expression. Trastuzumab stimulated sustained p38 activation and SB203580 attenuated the TSP-1 upregulation induced by trastuzumab. HER2 signaling therefore influences the equilibrium between pro-and antiangiogenic factors via distinct signaling pathways. Trastuzumab inhibits angiogenesis and tumor growth, at least in part, through activation of the HER2-p38-TSP-1 pathway and inhibition of the HER2-PI3K-AKT-VEGF/IL-8 pathway.

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Section: Introductionmentioning

confidence: 69%

HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

et al. 2006

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“…This indicates that a clinically relevant concentration (5B200 nM) of paclitaxel is sufficient to kill E1A-expressing cells, but parental cells require much higher dosage, which may be difficult to be achieved in a clinical setting. 42 We have previously shown that Her-2/neu-overexpressing cells are resistant to paclitaxel-induced apoptosis 43,44 and E1A, through downregulation of Her-2/neu, can sensitize cellular response to paclitaxel-induced apoptosis. 22,23,43,44 In those studies, we could not detect E1A-mediated chemosensitization in the low Her-2/neu-expressing cells.…”

Section: Discussionmentioning

confidence: 99%

“…42 We have previously shown that Her-2/neu-overexpressing cells are resistant to paclitaxel-induced apoptosis 43,44 and E1A, through downregulation of Her-2/neu, can sensitize cellular response to paclitaxel-induced apoptosis. 22,23,43,44 In those studies, we could not detect E1A-mediated chemosensitization in the low Her-2/neu-expressing cells. 22 The major reason for this discrepancy was due to the paclitaxel concentrations tested.…”

Section: Discussionmentioning

confidence: 99%

Enhanced paclitaxel cytotoxicity and prolonged animal survival rate by a nonviral-mediated systemic delivery of E1A gene in orthotopic xenograft human breast cancer

et al. 2004

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Paclitaxel (Taxol) is a promising frontline chemotherapeutic agent for the treatment of human breast and ovarian cancers. The adenoviral type 5 E1A gene has been tested in multiple clinical trials for its anticancer activity. E1A has also been shown to sensitize paclitaxel-induced killing in E1A-expressing cells. Here, we show that E1A can sensitize paclitaxel-induced apoptosis in breast cancer cells in a gene therapy setting by an orthotopic mammary tumor model. We first showed that expression of E1A enhanced in vitro paclitaxel cytotoxicity, as compared to the control cells. We then compared the therapeutic efficacy of paclitaxel between orthotopic tumor models established with vector-transfected MDA-MB-231 (231-Vect) versus 231-E1A stable cells, using tumor weight and apoptotic index (TUNEL assay) as the parameters. We found paclitaxel was more effective in shrinking tumors and inducing apoptosis in tumor models established with stable 231-E1A cells than the control 231-Vect cells. We also tested whether E1A could directly enhance paclitaxel-induced killing in nude mice, by using a nonviral, surface-protected cationic liposome to deliver E1A gene via the mouse tail vein. We compared the therapeutic effects of E1A gene therapy with or without Taxol chemotherapy in the established orthotopic tumor model of animals inoculated with MDA-MB-231 cells, and found that a combination of systemic E1A gene therapy and paclitaxel chemotherapy significantly enhanced the therapeutic efficacy and dramatically repressed tumor growth (Po.01). In addition, survival rates were significantly higher in animals treated with combination therapy than in the therapeutic control groups (both Po.0001). Thus, the E1A gene therapy indeed enhances the sensitivity of tumor cells to chemotherapy in a gene therapy setting and, the current study provides preclinical data to support combination therapy between E1A gene and chemotherapy for future clinical trials.

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“…First, erbB2 alterations enhance the ability of a cancer cell to invade and metastasize. Second, overexpression of erbB2 is associated with an increase in therapeutic resistance to tamoxifen and some chemotherapeutic agents, such as methotrexate and paclitaxel (Yu and Hung, 2000). The erbB2 receptor is therefore an ideal target for breast cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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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.

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Overexpression of ErbB2 in cancer and ErbB2-targeting strategies

Cited by 369 publications

References 66 publications

HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

Enhanced paclitaxel cytotoxicity and prolonged animal survival rate by a nonviral-mediated systemic delivery of E1A gene in orthotopic xenograft human breast cancer

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

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