Inhibition of Breast and Ovarian Tumor Growth through Multiple Signaling Pathways by Using Retrovirus-mediated Small Interfering RNA against Her-2/neu Gene Expression

Yang, Gong; Cai, Kathy Q.; Thompson-Lanza, Jennifer A.; Bast, Robert C.; Liu, Jinsong

doi:10.1074/jbc.m311153200

Cited by 105 publications

(91 citation statements)

References 39 publications

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“…The inhibitory effect of trastuzumab on the expression of VEGF and IL-8 was further confirmed by ELISA analysis ( Figure 2d and e). siHER2 delivered by retrovirus has been shown to specifically affect HER2 signaling (Yang et al, 2004). As expected, siHER2 diminished the level of HER2 protein (Figure 2a).…”

Section: Resultssupporting

confidence: 75%

“…TSP-1 is upregulated by trastuzumab treatment (Izumi et al, 2002). HER2 siRNA treatment of HER2-overexpressing BT474 cells also increases TSP-1 expression (Yang et al, 2004). Affymetrix microarray analysis indicated that treatment of BT474 cells with trastuzumab elevates TSP-1 expression (Le et al, 2005a).…”

Section: Discussionmentioning

confidence: 99%

“…Retrovirus-mediated small interfering RNA against HER2 A BT474 clone that stably expressed siHER2 was established as described previously (Yang et al, 2004).…”

Section: Cell Proliferation Assaymentioning

confidence: 99%

“…In an experimental model of human breast cancer, trastuzumab-induced normalization and regression of vasculature by modulating the expression of various pro-and antiangiogenic factors, including VEGF and TSP-1 (Izumi et al, 2002). With the aid of small interfering RNA (siRNA) against HER2 (siHER2), our group has also observed that inhibition of HER2 by siHER2 upregulates TSP-1 expression (Yang et al, 2004).…”

Section: Introductionmentioning

confidence: 98%

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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: Resultssupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

“…Retrovirus-mediated small interfering RNA against HER2 A BT474 clone that stably expressed siHER2 was established as described previously (Yang et al, 2004).…”

Section: Cell Proliferation Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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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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“…Construction of the destination vector, pDEST-CL-SI-MSCVpuro, for retroviral expression of shRNA, pCL-SI-MSCVpuro-ErbB2R-shRNA, -HPV16E6-shRNA, -p53-shRNA and -E6AP-shRNA was carried out by a previously described method (Sawada et al, 2004). The shRNA targeted sequences were as follows: HPV16E6: GTATGGAACAACATTAGAA, E6AP: 5 0 -GAAATCTAGT GAATGATGA-3 0 , p53 (18) and ErbB2 (Yang et al, 2004) as described previously. These entry vectors were recombined with pDEST-CL-SI-MSCVpuro by LR reactions (Invitrogen, Carlsbad, CA, USA), according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

HPV16 E6-mediated stabilization of ErbB2 in neoplastic transformation of human cervical keratinocytes

Narisawa‐Saito¹,

Handa²,

Yugawa³

et al. 2006

Oncogene

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Whether ErbB2 receptor tyrosine kinase contributes to cervical cancer is controversial. We have examined the effects of E6 and E7 genes of human papillomaviruses type 16 (HPV-16) on ErbB2 expression in primary human cervical keratinocytes (HCK) immortalized with hTERT (HCK1T). In E6-positive cells (HCK1T-E6 and HCK1T-E6E7), ErbB2 expression levels increased with the cell density. HCK1T-E6E7 showed impaired contact inhibition and anchorage-independent growth in soft agar which were abrogated with introduction of ErbB2-specific short hairpin RNA (shRNA) or an ErbB2 specific inhibitor AG825. Furthermore, increased ErbB2 expression was also observed in HPV16 positive cervical cancer cell lines and this was diminished by introduction of HPV16E6-or E6AP-shRNA. At post-confluence cell densities, ErbB2 protein was stabilized in the presence of E6 whereas increased ErbB2 expression was not obvious with E6 mutants incapable of degrading p53. Furthermore, introduction of p53-shRNA to HCK1T resulted in increased ErbB2 protein stability, indicating possible ErbB2 regulation through p53. Finally, we showed that tumor formation of ErbB2-shRNA introduced SiHa cells were almost abolished. Taken together, these data indicate an important role of ErbB2 regulation by HPV16 E6 in oncogenic transformation of human cervical keratinocytes.

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Targeting HER2 in patient‐derived xenograft ovarian cancer models sensitizes tumors to chemotherapy

et al. 2018

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Ovarian cancer is the most lethal gynecologic malignancy. About 75% of ovarian cancer patients relapse and/or develop chemo‐resistant disease after initial response to standard‐of‐care treatment with platinum‐based therapies. HER2 amplifications and overexpression in ovarian cancer are reported to vary, and responses to HER2 inhibitors have been poor. Next generation sequencing technologies in conjunction with testing using patient‐derived xenografts (PDX) allow validation of personalized treatments. Using a whole‐genome mate‐pair next generation sequencing (MPseq) protocol, we identified several high grade serous ovarian cancers (HGS‐OC) with DNA alterations in genes encoding members of the ERBB2 pathway. The efficiency of anti‐HER2 therapy was tested in three different PDX lines with the identified alterations and high levels of HER2 protein expression. Treatment responses to pertuzumab or pertuzumab/trastuzumab were compared in each PDX line WITH standard carboplatin and paclitaxel combination treatment. In all three PDX models, HER2‐targeted therapy resulted in significant inhibition of tumor growth compared with untreated controls. However, the responses in each case were inferior to those to chemotherapy, even for chemo‐resistant lines. When chemotherapy and HER2‐targeted therapy were administered together, a significant regression of tumor was observed after 6 weeks of treatment compared with chemotherapy alone. Post‐treatment analysis of these tissues revealed that inhibition of the ERBB2 pathway occurred at the level of phosphorylation and expression of downstream targets. In conclusion, while targeting of presumably activated ERBB2 pathway alone in HGS‐OC results in a modest treatment benefit, a combination therapy including both chemotherapy drugs and HER2 inhibitors provides a far better response. Further studies are needed to address development of recurrence and sensitivity of recurrent disease to HER2‐targeted therapy.

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Inhibition of Breast and Ovarian Tumor Growth through Multiple Signaling Pathways by Using Retrovirus-mediated Small Interfering RNA against Her-2/neu Gene Expression

Cited by 105 publications

References 39 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

HPV16 E6-mediated stabilization of ErbB2 in neoplastic transformation of human cervical keratinocytes

Targeting HER2 in patient‐derived xenograft ovarian cancer models sensitizes tumors to chemotherapy

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