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

Summary, in 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.

• Author: Karolina Helczynska; Anna-Maria Larsson; Linda Holmquist Mengelbier; Esther Bridges Baxter; Erik Fredlund; Signe Borgquist; Göran Landberg; Sven Påhlman; Karin Jirström
• Department/s: Department of Translational Medicine; Pathology, Malmö; Tumor microenvironment
• Publishing year: 2008
• Language: English
• Pages: 9212-9220
• Publication/Series: Cancer Research
• Volume: 68
• Issue: 22
• Links: http://www.ncbi.nlm.nih.gov/pubmed/19010893?dopt=Abstract; http://dx.doi.org/10.1158/0008-5472.CAN-08-1135
• Document type: Journal article
• Publisher: American Association for Cancer Research Inc.
• Topic: Cancer and Oncology
• Status: Published
• Research group: Pathology, Malmö
• ISBN/ISSN/Other: ISSN: 1538-7445