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

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)9212-9220
JournalCancer Research
Volume68
Issue number22
DOIs
Publication statusPublished - 2008

Bibliographical note

The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Molecular Medicine (013031200), Pathology (Malmö) (013031000), Pathology, (Lund) (013030000)

Subject classification (UKÄ)

  • Cancer and Oncology

Fingerprint

Dive into the research topics of 'Hypoxia-inducible factor-2alpha correlates to distant recurrence and poor outcome in invasive breast cancer.'. Together they form a unique fingerprint.

Cite this