ErbB2 Increases Vascular Endothelial Growth Factor Protein Synthesis via Activation of Mammalian Target of Rapamycin/p70S6K Leading to Increased Angiogenesis and Spontaneous Metastasis of Human Breast Cancer Cells

Klos, Kristine S.; Wyszomierski, Shannon L.; Sun, Menghong; Tan, Ming; Zhou, Xiaoyan; Li, Ping; Yang, Wentao; Yin, Guosheng; Hittelman, Walter N.; Yu, Dihua

doi:10.1158/0008-5472.can-04-4559

Cited by 175 publications

(139 citation statements)

References 50 publications

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“…In tumor cells, HER signaling induces a transcriptional program leading to the expression of a number of angiogenic factors (36), and specifically induces the expression and secretion of VEGF through pathways that include mTOR and HIF-1 (18,19), and the expression and activity of angiogenic matrix metalloproteinases (37). In endothelial cells, HER kinases promote angiogenic signaling that is independent of VEGF signaling (38,39).…”

Section: Discussionmentioning

confidence: 99%

Improved tumor vascular function following high‐dose epidermal growth factor receptor tyrosine kinase inhibitor therapy

Moasser

Wilmes

Wong

et al. 2007

Magnetic Resonance Imaging

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Purpose: To determine if inhibitors of the human growth factor receptor (HER) family can be used to enhance tumor vascular permeability and perfusion and optimize the efficacy of cytotoxic chemotherapeutics. Poor tumor vascular function limits the delivery and efficacy of cancer chemotherapeutics and HER family tyrosine kinases mediate tumor-endothelial signaling in both of these compartments. Materials and Methods:BT474 human breast cancer tumors were established in mice and the biologic effects of the HER tyrosine kinase inhibitor (TKI) gefitinib on tumor vascular function was determined by dynamic contrast-enhanced MRI (DCE-MRI), and on tumor vascular architecture and perfusion by immunofluorescence microscopy. Results:A brief dose of gefitinib enhances the antitumor activity of paclitaxel in vivo but not in cell culture, suggesting that its chemoenhancing activity involves the in vivo microenvironment. A brief high dose of gefitinib induces a decrease in endothelial transfer constant (Kps) and a concomitant increase in tumor fractional plasma volume (fPV). These changes are accompanied by a rapid reduction in tumor volume, likely due to decreased tumor edema, and modestly improved tumor vascular architecture and perfusion on microscopy. Conclusion:These data suggest that HER family TKIs have the potential to optimize the tumor microenvironment for delivery of cytotoxic chemotherapeutics.

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Section: Discussionmentioning

confidence: 99%

Improved tumor vascular function following high‐dose epidermal growth factor receptor tyrosine kinase inhibitor therapy

Moasser

Wilmes

Wong

et al. 2007

Magnetic Resonance Imaging

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“…This kinase regulates the efficiency of translation of certain mRNAs and also functions in a negative feedback loop to control Akt activity (Chiang and Abraham, 2005;Inoki et al, 2005;Martelli et al, 2007). Akt, mTOR and p70S6K activation have been associated with a more severe prognosis in breast and other cancers (Bose et al, 2002;Clark et al, 2002;DeGraffenried et al, 2004;Nagata et al, 2004;Lin et al, 2005;Tsutsui et al, 2005a, b;Klos et al, 2006;Tokunaga et al, 2006;Martelli et al, 2007). Targeting the PI3K/Akt/mTOR pathway may prove effective in various cancer therapies (Martelli et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Suppression of PTEN function increases breast cancer chemotherapeutic drug resistance while conferring sensitivity to mTOR inhibitors

et al. 2008

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Ectopic expression of mutant forms of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) lacking lipid (G129E) or lipid and protein (C124S) phosphatase activity decreased sensitivity of MCF-7 breast cancer cells, which have wild-type PTEN, to doxorubicin and increased sensitivity to the mammalian target of rapamycin (mTOR) inhibitor rapamycin. Cells transfected with a mutant PTEN gene lacking both lipid and protein phosphatase activities were more resistant to doxorubicin than cells transfected with the PTEN mutant lacking lipid phosphatase activity indicating that the protein phosphatase activity of PTEN was also important in controlling the sensitivity to doxorubicin, while no difference was observed between the lipid (G129E) and lipid and protein (C124S) phosphatase PTEN mutants in terms of sensitivity to rapamycin. A synergistic inhibitory interaction was observed when doxorubicin was combined with rapamycin in the phosphatase-deficient PTENtransfected cells. Interference with the lipid phosphatase activity of PTEN was sufficient to activate Akt/mTOR/ p70S6K signaling. These studies indicate that disruption of the normal activity of the PTEN phosphatase can have dramatic effects on the therapeutic sensitivity of breast cancer cells. Mutations in the key residues which control PTEN lipid and protein phosphatase may act as dominant-negative mutants to suppress endogenous PTEN and alter the sensitivity of breast cancer patients to chemo-and targeted therapies.

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“…Previous studies demonstrating that the expression of p53 in tumor tissues was associated with the reduced disease-free interval with anti-VEGF monoclonal antibody (Klos et al, 2006;Murad et al, 2007;Li et al, 2011).…”

Section: Discussionmentioning

confidence: 93%

Analysis of PTEN, VEGF, HER2 and P53 Status in Determining Colorectal Cancer Benefit from Bevacizumab Therapy

Kara

Duman²,

Kara³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Background: No factor has thus far been identified to predict the efficacy of bevacizumab therapy for colorectal cancer. We here therefore studied PTEN, VEGF, HER2 and p53 by immunohistochemistry as possible prognostic and predictive factors. Materials and Methods: A total of 34 retrospectively collected tumor samples were evaluated, all from patients receiving bevacizumab-based regimens. VEGF-A, PTEN, HER2, p53 were assessed and data was compared with clinicopathologic characteristics of patients and the bevacizumab response rate. Results: In this study, the median age of the 34 metastatic colorectal cancer patients was 55.5 (24-75), twelve (35.3%) being women and 22 (64.7%) men. PTEN, VEGF, HER2, p53 expressions were compared with bevacizumab response and other chacteristics of disease. Statistical significant differences were not found between bevacizumab response rates and different expression levels of VEGF, PTEN, HER2 and p53 (respectively p=0.256, p=0.832, p=0.189, p=0.131). However, a survival difference was noted in the VEGF expression negative group (median OS:55 months; 95%CI, 22-88 months) (p=0.01). There was no statistically significant OS difference in other groups (PTEN p=0.6, HER2 p=0.189, p53 p=0.13). Conclusions: We did not find any predictive factor for BV therapy in our study. VEGF negative expression could be an important prognostic factor in metastatic colorectal carcinoma.

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ErbB2 Increases Vascular Endothelial Growth Factor Protein Synthesis via Activation of Mammalian Target of Rapamycin/p70S6K Leading to Increased Angiogenesis and Spontaneous Metastasis of Human Breast Cancer Cells

Cited by 175 publications

References 50 publications

Improved tumor vascular function following high‐dose epidermal growth factor receptor tyrosine kinase inhibitor therapy

Improved tumor vascular function following high‐dose epidermal growth factor receptor tyrosine kinase inhibitor therapy

Suppression of PTEN function increases breast cancer chemotherapeutic drug resistance while conferring sensitivity to mTOR inhibitors

Analysis of PTEN, VEGF, HER2 and P53 Status in Determining Colorectal Cancer Benefit from Bevacizumab Therapy

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