HER2 (neu) Signaling Increases the Rate of Hypoxia-Inducible Factor 1α (HIF-1α) Synthesis: Novel Mechanism for HIF-1-Mediated Vascular Endothelial Growth Factor Expression

Laughner, Erik; Taghavi, Panthea; Chiles, Kelly A.; Mahon, Patrick C.; Semenza, Gregg L.

doi:10.1128/mcb.21.12.3995-4004.2001

Cited by 1,185 publications

(1,040 citation statements)

References 63 publications

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“…Several dozens of HIF-1 targets are known, including the genes encoding VEGF and IGF-II. The relationship of HIF-1 with bFGFR has also been described (Kim et al, 1998;Semenza, 1999;Giatromanolaki et al, 2001;Laughner et al, 2001).…”

Section: Discussionmentioning

confidence: 88%

“…In this regard, previous studies have shown that Gq-coupled receptors such as those for bombesin/ GRP can phosphorylate receptors of the ErbB/HER family by transactivation (Prenzel et al, 1999). It has also been revealed that EGFR and HER-2 can potentiate tumour cell adhesion to endothelial cells, by enhancing the synthesis of hypoxia-inducible factor (HIF)-1a, and/or carbonic anhydrase-9 (Giatromanolaki et al, 2001;Laughner et al, 2001) through a PI3 kinase-dependent pathway (Bagheri-Yarmand et al, 2000). Several dozens of HIF-1 targets are known, including the genes encoding VEGF and IGF-II.…”

Section: Discussionmentioning

confidence: 99%

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Bombesin antagonists inhibit proangiogenic factors in human experimental breast cancers

et al. 2004

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The overexpression of angiogenic factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and insulin-like growth factors (IGFs) plays a role in the migration and proliferation of endothelial cells in many cancers. Consequently, we investigated the effects of bombesin/gastrin-releasing peptide (GRP) antagonists on the expression of these angiogenic factors, the activities of matrix metalloproteinases (MMPs)-2 and -9, as well as the vascular density in MDA-MB-435 human oestrogenindependent breast cancers. Nude mice bearing orthotopic xenografts of MDA-MB-435 breast cancers were treated with bombesin/ GRP antagonists for 6 weeks. Daily administration of 20 mg of RC-3095 or 10 mg of RC-3940-II significantly decreased the weight of MDA-MB-435 cancers by 44 and 53%, respectively. The inhibition of tumour growth was associated with a substantial reduction in the expression of mRNA and protein levels of basic fibroblast growth factor (bFGF), IGF-II and VEGF-A in the tumours. Both bombesin/GRP antagonists significantly decreased the vessel density of the tumours by about 37%, as shown by immunohistochemical detection of vessels on tumour slides. Gelatinolytic activities, detected by zymography, revealed a 33 -46% reduction in MMP-9 activity after the treatment with either antagonist. In vitro studies revealed that MDA-MB-435 cells secrete bFGF, IGF-II and VEGF-A, and the secretion of these factors is inhibited by RC-3095 and RC-3940-II. This study demonstrates the antiangiogenic effect of bombesin/GRP antagonists RC-3095 and RC-3940-II, and underscores their possible therapeutic application for treatment of breast cancers.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Bombesin antagonists inhibit proangiogenic factors in human experimental breast cancers

et al. 2004

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“…21 Loss-of-function mutations in the tumor suppressor genes encoding p53, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and VHL also result in increased HIF-1␣ expression in human malignancies. Whether levels of HIF-1␣ represent the degree of cellular hypoxia or mainly point to oncogene activation has not been elucidated to date.…”

Section: Discussionmentioning

confidence: 99%

“…21 To date, a few studies, all based on a relatively small number of patients, have investigated the prognostic relevance of HIF-1 in human solid tumors, and none of those studies compared this relevance with that of HER-2/neu amplification. In patients with early cervical carcinoma (n ϭ 91 patients), 22 oropharyngeal carcinoma (n ϭ 98 patients), 23 oligodendrogliomas (n ϭ 51 patients), 24 and nonsmall cell lung carcinomas (n ϭ 108 patients), 25 high levels of HIF-1␣ predicted poor prognosis; however, the opposite was reported for lung carcinoma (n ϭ 55 patients) 26 and head and neck squamous cell carcinoma (n ϭ 69 patients), 27 whereas no effect on survival was noticed in patients with ovarian carcinoma (n ϭ 60 patients).…”

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confidence: 99%

Levels of hypoxia‐inducible factor‐1α independently predict prognosis in patients with lymph node negative breast carcinoma

Bos

Groep

Greijer

et al. 2003

Cancer

Self Cite

465

362

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BACKGROUNDHypoxia‐inducible factor‐1 (HIF‐1) is a transcription factor that plays an important role in tumor growth and metastasis by regulating energy metabolism and inducing angiogenesis to survive cellular hypoxia. Increased levels of HIF‐1α, the O2‐regulated subunit of HIF‐1, were noted during breast carcinogenesis. In this study, the prognostic value of HIF‐1α expression and its correlation with various clinicopathologic variables in patients with invasive breast carcinoma were investigated.METHODSExpression levels of HIF‐1α, HER‐2/neu, estrogen receptor, and progesterone receptor were analyzed in 150 patients with early‐stage breast carcinoma by immunohistochemistry. HER‐2/neu gene amplification was investigated with automated fluorescent in situ hybridization. The mitotic activity index, histologic grade, and tumor type were assessed in hematoxylin and eosinstained specimens. Clinical data included disease‐free survival, overall survival, lymph node status, and tumor size. The data were analyzed with two‐sided univariate and multivariate tests, with P values < 0.05 considered significant.RESULTSHigh levels of HIF‐1α had an association of borderline significance with decreased overall survival (P = 0.059) and disease‐free survival (P = 0.110) that was ascribed completely to the subgroup of women with lymph node negative tumors (n = 81 patients; P = 0.008 and P = 0.004, respectively). HER‐2/neu immunoreactivity (P < 0.001) and gene amplification (P < 0.001), vascular endothelial growth factor expression (P = 0.016), and Ki‐67 expression (P < 0.001) were correlated strongly with HIF‐1α positivity, although none of those factors had an independent effect on survival.CONCLUSIONSIncreased levels of HIF‐1α were associated independently with shortened survival in patients with lymph node negative breast carcinoma. Therefore, the use of immunohistochemical assessment of HIF‐1α as a new predictor of poor outcome may improve clinical decision‐making regarding adjuvant treatment of patients with lymph node negative breast carcinoma. Cancer 2003;97:1573–81. © 2003 American Cancer Society.DOI 10.1002/cncr.11246

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“…However, under hypoxic conditions, HIF-1a degradation is inhibited, thereby resulting in an increase in the level of HIF-1a protein and the subsequent upregulation of VEGF transcription (Shweiki et al, 1992). In other tumor models, mTOR inhibitors downregulate angiogenesis by inhibiting HIF-1 expression that was not due to affects on HIF protein stability (Laughner et al, 2001). In contrast, in our myeloma model, there were no effects of mTOR inhibitors on VEGF mRNA levels under normoxic conditions, indicating that alterations in HIF-1 did not play a role in the depressed VEGF protein levels.…”

Section: Discussionmentioning

confidence: 99%

AKT activity regulates the ability of mTOR inhibitors to prevent angiogenesis and VEGF expression in multiple myeloma cells

Frost¹,

Shi²,

Hoang³

et al. 2006

Oncogene

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We recently demonstrated that the mammalian target of rapamycin (mTOR) inhibitor, CCI-779, curtailed the growth of a subcutaneous challenge of multiple myeloma (MM) cells in immunodeficient mice. This antitumor effect was associated with prevention of cell proliferation, induction of apoptosis and inhibition of angiogenesis. Interestingly, myeloma tumors with heightened AKT activation were particularly sensitive to a CCI-779-induced antitumor response. To investigate whether part of the differential sensitivity was due to an AKT-regulated effect on angiogenesis, we compared the effects of mTOR inhibitors against isogenic MM cell lines that only differ by their degree of AKT activity. In this model, heightened AKT activity significantly sensitized MM cells to the following inhibitory effects of mTOR inhibition: angiogenesis in vivo, vascular endothelial growth factor (VEGF) expression in vitro and in vivo and VEGF translation (but not transcription). Assessment of p70S6 kinase activity indicated that rapamycin induced comparable mTOR inhibition in both cell lines suggesting that an adverse effect on VEGF cap-dependent translation would be comparable. Internal ribosome entry site (IRES)-mediated cap-independent translation is a salvage pathway for protein expression when mTOR is inhibited, so we analyzed a possible regulatory role of AKT on VEGF IRES activity. We found that elevated AKT activity inhibited VEGF IRES function. These results support a mechanism whereby AKT prevents VEGF IRES activity in myeloma cells during mTOR inhibition resulting in a more complete abrogation of VEGF translation, and ultimately, angiogenesis.

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HER2 (neu) Signaling Increases the Rate of Hypoxia-Inducible Factor 1α (HIF-1α) Synthesis: Novel Mechanism for HIF-1-Mediated Vascular Endothelial Growth Factor Expression

Cited by 1,185 publications

References 63 publications

Bombesin antagonists inhibit proangiogenic factors in human experimental breast cancers

Bombesin antagonists inhibit proangiogenic factors in human experimental breast cancers

Levels of hypoxia‐inducible factor‐1α independently predict prognosis in patients with lymph node negative breast carcinoma

AKT activity regulates the ability of mTOR inhibitors to prevent angiogenesis and VEGF expression in multiple myeloma cells

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