High eIF4E, VEGF, and Microvessel Density in Stage I to III Breast Cancer

Byrnes, Kerry; White, Stephen G.; Chu, Quyen D.; Meschonat, Carol; Yu, Herbert; Johnson, Lester W.; DeBenedetti, Arrigo; Abreo, Fleurette; Turnage, Richard H.; McDonald, John C.; Li, Benjamin D.

doi:10.1097/01.sla.0000216770.23642.d8

Cited by 54 publications

(38 citation statements)

References 27 publications

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“…Uzzan et al (14) found that high MVD predicted poor survival [RR, 1.99 for RFS (95% CI, 1.33-2.98) and RR, 1.54 for OS (95% CI, 1.01-2.33)], and MVD may be a better prognostic factor when assessed by CD31 or CD34. Byrnes et al (15) drew the similar conclusion that high VEGF levels and MVD always led to poor clinical prognosis.…”

Section: Discussionmentioning

confidence: 91%

Inhibitory effect of endostatin combined with paclitaxel-cisplatin on breast cancer in xenograft-bearing mice

Sun

Deng

Duan

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. In the present study, we aimed to investigate the tumor-inhibiting effects of recombinant human endostatin (rhES) combined with paclitaxel-cisplatin (TP regimen) on human breast cancer in xenograft-bearing nude mice. A total of 24 mice bearing human breast cancer xenografts were administered both rhES and TP, TP alone, rhES alone or saline. The tumor growth inhibition was observed. Serum vascular endothelial growth factor (VEGF) levels and microvessel density (MVD) were determined by ELISA and immunohistochemistry, respectively. Cell apoptosis was detected using terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) staining. Survival time was observed in another 24 nude mice with the same treatment. MVD expression in the group administered rhES and TP was lower than that in the other groups (P<0.05); serum VEGF levels in the combined drug group were lower compared to the other groups; the apoptotic index increased in the combined drug group. We conclude that the effect of the TP regimen combined with rhES on breast cancer is better than that of the TP regimen alone.

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Section: Discussionmentioning

confidence: 91%

Inhibitory effect of endostatin combined with paclitaxel-cisplatin on breast cancer in xenograft-bearing mice

Sun

Deng

Duan

et al. 2011

Experimental and Therapeutic Medicine

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“…mTor and its downstream effector p70-S6 kinase are both expressed and activated at high levels in invasive human breast carcinomas, and both of these signaling molecules are associated with an increased risk for disease recurrence (7,35,76,87). Expression of the translation initiator eIF4E is also upregulated in human cancers, including breast, and it has been linked to metastasis (8,58). In the absence of Irs-1, mouse mammary tumors exhibit increased activity of all of these signaling molecules, confirming that at the molecular level, loss of Irs-1 closely mimics the progression of human breast cancer to metastatic disease.…”

Section: Discussionmentioning

confidence: 99%

Suppression of Insulin Receptor Substrate 1 (IRS-1) Promotes Mammary Tumor Metastasis

Gibson

Byrne

et al. 2006

Molecular and Cellular Biology

100

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The insulin receptor substrate (IRS) proteins are cytoplasmic adaptors that organize signaling complexes downstream of activated cell surface receptors. Here, we show that IRS-1 and IRS-2, despite significant homology, play critical yet distinct functions in breast cancer, and we identify specific signaling pathways that are influenced by IRS-1 using the polyoma virus middle-T (PyV-MT) transgenic mouse model of mammary carcinoma and Irs-1 null (Irs1 ؊/؊ ) mice. The absence of Irs-1 expression enhanced metastatic spread significantly without a significant effect on primary tumor growth. Orthotopic transplant studies revealed that the increased metastatic potential of Irs1-deficient tumor cells is cell autonomous. Mammary tumors that developed in PyV-MT::Irs1 ؊/؊ mice exhibited elevated Irs-2 function and enhanced phosphatidylinositol 3-kinase/ Akt/mTor activity, suggesting that one mechanism by which Irs-1 impedes metastasis is to suppress Irs-2-dependent signaling. In support of this mechanism, reduction of Irs-2 expression in Irs1 ؊/؊ tumor cells restored mTor signaling to wild-type levels. PyV-MT::Irs1 ؊/؊ tumors also exhibited a significant increase in vascular endothelial growth factor expression and microvessel density, which could facilitate their dissemination. The significance of our findings for human breast cancer is heightened by our observation that Irs-1 is inactivated in wild-type, metastatic mammary tumors by serine phosphorylation. Collectively, our findings reveal that inactivation of IRS-1 enhances breast cancer metastasis and support the novel hypothesis that IRS-1 has metastasis suppressor functions for breast cancer.The insulin receptor substrate (IRS) proteins are cytoplasmic docking proteins that function as essential signaling intermediates downstream of activated cell surface receptors, including the insulin, insulin-like growth factor 1 (IGF-1), prolactin, growth hormone (GH), and vascular endothelial growth factor (VEGF) receptors, members of the integrin receptor family, and select cytokine receptors (38,68,70,78,81,85). The IRS proteins are recruited to receptors through pleckstrin homology and phosphotyrosine-binding domains in their N termini and mediate their functions by organizing signaling complexes at sites of receptor activation (81). Upon binding they are phosphorylated on tyrosine residues in their C termini, creating multiple phosphotyrosine binding motifs that recruit downstream effectors, including phosphatidylinositol 3-kinase (PI3K), Grb-2, Fyn, and Shp-2 to initiate intracellular signaling cascades (81). The IRS proteins were originally identified as substrates of the insulin receptor, and they have been predominantly studied for their role in metabolic signaling (81). Although the IRS proteins are highly homologous, there is evidence for unique functions for each of the four IRS family members. Irs-1 null mice are born small and remain runted throughout life, and these mice develop insulin resistance. However, Irs-1 null mice do not develop diabetes, because they mai...

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“…VEGF was initially identified in 1983 as a protein secreted by tumor cells [15] . It is one of the most potent angiogenic factors expressed in various human cancers [16,17] . As an endothelial growth factor, VEGF stimulates endothelial cell proliferation, thus inducing the budding of new blood vessels around the growing tumor masses.…”

Section: Discussionmentioning

confidence: 99%

Impact of serum vascular endothelial growth factor on prognosis in patients with unresectable hepatocellular carcinoma after transarterial chemoembolization

Guo

Zhu

et al. 2012

Chin. J. Cancer Res.

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Objective: To investigate the expression level of serum vascular endothelial growth factor (VEGF) in patients with unresectable hepatocellular carcinoma (HCC) and its relationship with the clinicopathological characteristics, and to assess the impact of serum VEGF as a predictive factor for HCC prognosis during transarterial chemoembolization (TACE) treatments.Methods: Serum VEGF levels were measured using enzyme-linked immunosorbent assay (ELISA) in 60 random patients who underwent TACE or transarterial infusion (TAI) for unresectable HCC between May and September 2008 and 12 healthy volunteers were also involved in this study to serve as control. All patients' clinicopathological features were retrospectively analyzed. Serum VEGF levels were correlated with clinicopathological features of the HCC patients. The patients' survival rates were analyzed with Kaplan-Meier survival curves and compared by the log-rank test. The prognostic significance of serum VEGF levels and factors related to survival rate were evaluated by univariate and multivariate analysis.Results: The median serum VEGF level in the HCC patients was 285 pg/ml (range 14−1,207 pg/ml), significantly higher than that of healthy controls (P=0.021). The serum VEGF levels were significantly correlated with platelet counts (r=0.396, P=0.002) but not other clinicopathological features. Patients with serum VEGF level >285 pg/ml had worse overall survival compared with those with serum VEGF level <285 pg/ml (P=0.002). By multivariate analysis, the serum VEGF level was a significant prognostic factor.Conclusion: High serum VEGF levels may predict poor prognosis of HCC after TACE. This study highlights the importance of tumor biomarker as a prognostic predictor in TACE therapy for HCC, which has an intrinsic problem of unavailability of histopathological prognostic features.

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High eIF4E, VEGF, and Microvessel Density in Stage I to III Breast Cancer

Cited by 54 publications

References 27 publications

Inhibitory effect of endostatin combined with paclitaxel-cisplatin on breast cancer in xenograft-bearing mice

Inhibitory effect of endostatin combined with paclitaxel-cisplatin on breast cancer in xenograft-bearing mice

Suppression of Insulin Receptor Substrate 1 (IRS-1) Promotes Mammary Tumor Metastasis

Impact of serum vascular endothelial growth factor on prognosis in patients with unresectable hepatocellular carcinoma after transarterial chemoembolization

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