Hypoxia-Inducible Factor-2α Correlates to Distant Recurrence and Poor Outcome in Invasive Breast Cancer

Helczynska, Karolina; Larsson, Anna-Maria; Mengelbier, Linda Holmquist; Bridges, Esther; Fredlund, Erik; Borgquist, Signe; Landberg, Göran; Påhlman, Sven; Jirström, Karin

doi:10.1158/0008-5472.can-08-1135

Cited by 129 publications

(131 citation statements)

References 39 publications

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“…In cell lines, both HIFs are expressed and hypoxia-regulated. Similar to the situation in neuroblastoma, HIF-1α is acutely and transiently upregulated, whereas HIF-2α protein is still present after prolonged hypoxia and appears to mediate a sustained hypoxic response, including expression of VEGF (Helczynska et al 2008). Expression in tumors and association of HIFs to breast cancer aggressiveness appear to be a complex issue.…”

Section: Differential Tumor Hif Expression In Relation To Patient Outmentioning

confidence: 79%

“…For historical reasons, HIF-1α is the isoform that has been most extensively studied in clinical tumor materials and frequently been correlated with aggressive tumor disease, but in recent years high tumor levels of HIF-2α rather than HIF-1α have been shown to associate with negative overall survival and metastatic disease. In, for instance, breast carcinoma, earlier published data link HIF-1α, while later reports link HIF-2α to unfavorable disease (Schindl et al 2002;Bos et al 2003;Gruber et al 2004;Dales et al 2005;Generali et al 2006;Giatromanolaki et al 2006;Kronblad et al 2006;Helczynska et al 2008). Whether these contradicting observations reflect real differences in the tumor material analyzed, or can be attributed to methodological shortcomings is presently unknown.…”

Section: Hypoxia In Solid Tumors and Relation To Tumor Aggressivenessmentioning

confidence: 99%

“…In tumor cell lines, with few exceptions both HIF-1α and HIF-2α are expressed, and we recently postulated that HIF-1α is involved in adaptation to acute, and HIF-2α to prolonged, hypoxia (Holmquist-Mengelbier et al 2006;Helczynska et al 2008). For historical reasons, HIF-1α is the isoform that has been most extensively studied in clinical tumor materials and frequently been correlated with aggressive tumor disease, but in recent years high tumor levels of HIF-2α rather than HIF-1α have been shown to associate with negative overall survival and metastatic disease.…”

Section: Hypoxia In Solid Tumors and Relation To Tumor Aggressivenessmentioning

confidence: 99%

“…Early studies on HIF-1α protein expression in various subgroups of breast cancers link high levels of the protein to poor outcome, although several of these reports contradict each other. In more recent studies, the overall relationship between HIF-1α protein and breast-cancer-specific death is meager, and HIF-1α associates positively rather than negatively to favorable disease (Tan et al 2007;Helczynska et al 2008). However, there are early reports correlating high HIF-1α protein expression with shorter overall and disease-free survival time in patients with lymph node-positive breast cancer, whereas this association was not significant in lymph-node negative patients (Schindl et al 2002;Kronblad et al 2006).…”

Section: Differential Tumor Hif Expression In Relation To Patient Outmentioning

confidence: 99%

“…Importantly, and the reason for the focus on HIF-2α in this review, HIF-1α and HIF-2α are differently regulated in tumors such as neuroblastoma, breast cancer, non-small cell lung carcinoma (NSCLC) and glioma and seem to have different impact on tumor behavior and patient outcome in these tumors (Holmquist-Mengelbier et al 2006;Helczynska et al 2008;Heddleston et al 2009;Kim et al 2009b;Li et al 2009;Noguera et al 2009). …”

Section: Introductionmentioning

confidence: 99%

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The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

Pietras

Johnsson

Påhlman

2010

Current Topics in Microbiology and Immunology

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Section: Differential Tumor Hif Expression In Relation To Patient Outmentioning

confidence: 79%

Section: Hypoxia In Solid Tumors and Relation To Tumor Aggressivenessmentioning

confidence: 99%

Section: Hypoxia In Solid Tumors and Relation To Tumor Aggressivenessmentioning

confidence: 99%

Section: Differential Tumor Hif Expression In Relation To Patient Outmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

Pietras

Johnsson

Påhlman

2010

Current Topics in Microbiology and Immunology

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Synthesis and study of new radial organic/inorganic hybrid epoxides

Herr¹,

Chaplinsky²,

Romanelli³

et al. 2007

J of Applied Polymer Sci

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A new approach to the synthesis of reactive organic/inorganic hybrid molecules was developed. Alternating hydrocarbon and siloxane segments were introduced into the arms of radial oligomers using hydrosilation chemistry. Cycloaliphatic and glycidyl epoxy-terminal systems with bisphenol A-based aromatic hydrocarbon cores and siloxane units derived from 1,1,3,3-tetramethyldisiloxane were synthesized and fully characterized (molecules 7 and 6, respectively). The cationic UV and thermal curing behavior of these two new radial hybrid epoxies was investigated using photo-and thermal-differential scanning calorimetry. Hybrid cycloaliphatic epoxy 7 exhibited good UV curing kinetics and photopolymerized to high conversion. The glycidyl analog 6 exhibited poor UV curing kinetics, but was readily cured using 2-ethyl-4-methylimidazole as a nucleophilic curing agent. Both hybrid epoxysiloxanes exhibited extensive thermal cationic cure. The physical properties of cured films of the two new radial epoxysiloxanes were studied and compared with various commercially available hydrocarbon and siloxane benchmark materials. The cured systems exhibited lower moisture uptake and better thermal stability than most hydrocarbon epoxies examined. Several visually compatible blends of the new hybrid molecules with common hydrocarbon resins were identified, and in general organic compatibility was found to be intermediate among selected siloxane-containing benchmarks. Molecules 6 and 7 represent progress towards the goal of synthesizing highly functional organic/inorganic hybrid molecules which combine the best attributes of both hydrocarbon epoxides and siloxane materials.

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Cysteinyl leukotriene receptor expression pattern affects migration of breast cancer cells and survival of breast cancer patients

Magnusson

Liu

Ehrnström

et al. 2010

Intl Journal of Cancer

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The fact that breast cancer patients with local or distal dissemination exhibit decreased survival, promotes a search for novel mechanisms to suppress such tumor progression. Here, we have determined the expression of proinflammatory cysteinyl leukotriene receptors (CysLTRs) in breast tumor tissue and their signaling effect on breast cancer cell functions related to tumor progression. Patients with breast tumors characterized by high CysLT 1 R and low CysLT 2 R expression levels exhibited increased risk of cancer-induced death in univariate analysis for both the total patient group (hazard ratio [HR] 5 2.88, 95% confidence interval [CI] 5 1.11-7.41), as well as patients with large (>20 mm) tumors (HR 5 5.08, 95% CI 5 1.39-18.5). Multivariate analysis revealed that patients with large tumors exhibiting high CysLT 1 R and low CysLT 2 R expression levels had a significantly reduced survival, also when adjusted for established prognostic parameters (HR 5 7.51, 95% CI 5 1.83-30.8).In patients with large (>20 mm) tumors, elevated CysLT 2 R expression predicted an improved 5-year survival (log-rank test p 5 0.04). Surprisingly, for longer time periods, this prognostic value was lost. This disappearance coincided with the termination of hormonal treatment. Tamoxifen preserved and even induced transcription of CysLT 2 R, but not CysLT 1 R, in estrogene receptor-positive MCF-7 breast cancer cells. This elevated CysLT 2 R expression decreased, even below the level of untreated cells, when tamoxifen was withdrawn. CysLT 2 R signaling reduced MCF-7 cell migration, but had no effect on either proliferation or apoptosis. Our data indicate that low CysLT 1 R together with high CysLT 2 R expression levels might be useful parameters in prognostication and treatment stratification of breast cancer patients.Breast cancer is the most frequently diagnosed malignancy in women. 1 The prognosis is relatively good for patients without local or distal dissemination. However, the 5-year survival decreases considerably with the occurrence of metastasis. 2

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Hypoxia-Inducible Factor-2α Correlates to Distant Recurrence and Poor Outcome in Invasive Breast Cancer

Abstract: Differential regulation as well as target gene specificity of the two hypoxia-inducible factor

Cited by 129 publications

References 39 publications

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

Synthesis and study of new radial organic/inorganic hybrid epoxides

Cysteinyl leukotriene receptor expression pattern affects migration of breast cancer cells and survival of breast cancer patients

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