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Hypoxia-inducible factor-2alpha correlates to distant recurrence and poor outcome in invasive breast cancer.

  • Karolina Helczynska
  • Anna-Maria Larsson
  • Linda Holmquist Mengelbier
  • Esther Bridges Baxter
  • Erik Fredlund
  • Signe Borgquist
  • Göran Landberg
  • Sven Påhlman
  • Karin Jirström
Publishing year: 2008
Language: English
Pages: 9212-9220
Publication/Series: Cancer Research
Volume: 68
Issue: 22
Document type: Journal article
Publisher: American Association for Cancer Research Inc.

Abstract english

Differential regulation as well as target gene specificity of the two hypoxia-inducible factor (HIF)-alpha subunits HIF-1alpha and HIF-2alpha in various tumors and cell lines have been suggested. In breast cancer, the prognostic significance of HIF-1alpha is not clear-cut and that of HIF-2alpha is largely unknown. Using IHC analyses of HIF-1alpha, HIF-2alpha, and vascular endothelial growth factor (VEGF) expression in a tissue microarray of invasive breast cancer specimens from 512 patients, we investigated the expression patterns of the 2 HIF-alpha subunits in relation to established clinicopathologic variables, VEGF expression, and survival. HIF-1alpha and HIF-2alpha protein levels and their effect on survival were additionally analyzed in a second cohort of 179 patients. To evaluate the individual role of each subunit in the hypoxic response and induction of VEGF, HIF-alpha protein and HIF-alpha and VEGF mRNA levels were further studied in cultured breast cancer cells after hypoxic induction and/or knockdown of HIF-alpha subunits by siRNA by Western blot and Quantitative Real-Time PCR techniques. We showed that although HIF-1alpha and HIF-2alpha protein levels in breast cancer specimens were not interrelated, high levels of both HIF-1alpha and HIF-2alpha associated to high VEGF expression. HIF-2alpha expression was an independent prognostic factor associated to reduced recurrence-free and breast cancer-specific survival, whereas HIF-1alpha did not exhibit these correlations. In cultured cells, acute hypoxia induced both HIF-proteins. At prolonged hypoxia, HIF-2alpha remained accumulated, whereas HIF-1alpha protein levels decreased, in agreement with the oxygen level and time-dependent induction of HIFs recently reported in neuroblastoma.


  • Cancer and Oncology


  • CREATE Health
  • Pathology, Malmö
  • ISSN: 1538-7445
Sven Påhlman
E-mail: sven [dot] pahlman [at] med [dot] lu [dot] se


Division of Translational Cancer Research

+46 46 222 64 21

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