This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Helczynska, K. Articles by Jirström, K. Search for Related Content PubMed PubMed Citation Articles by Helczynska, K. Articles by Jirström, K.

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

¹ Center for Molecular Pathology, Department of Laboratory Medicine, ² CREATE Health, Lund University and ³ Department of Surgery, University Hospital MAS, Malmö, Sweden

Requests for reprints: Sven Påhlman, Center for Molecular Pathology, Department of Laboratory Medicine, Lund University, University Hospital MAS, Entrance 78, SE-205 02 Malmö, Sweden. Phone: 46-40337427; Fax: 46-40336073; E-mail: sven.pahlman{at}med.lu.se.

Key Words: breast cancer • hypoxia • HIF-1 • HIF-2 • prognosis

Differential regulation as well as target gene specificity of the two hypoxia-inducible factor (HIF)- subunits HIF-1 and HIF-2 in various tumors and cell lines have been suggested. In breast cancer, the prognostic significance of HIF-1 is not clear-cut and that of HIF-2 is largely unknown. Using IHC analyses of HIF-1, HIF-2, 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- subunits in relation to established clinicopathologic variables, VEGF expression, and survival. HIF-1 and HIF-2 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- protein and HIF- and VEGF mRNA levels were further studied in cultured breast cancer cells after hypoxic induction and/or knockdown of HIF- subunits by siRNA by Western blot and Quantitative Real-Time PCR techniques. We showed that although HIF-1 and HIF-2 protein levels in breast cancer specimens were not interrelated, high levels of both HIF-1 and HIF-2 associated to high VEGF expression. HIF-2 expression was an independent prognostic factor associated to reduced recurrence-free and breast cancer–specific survival, whereas HIF-1 did not exhibit these correlations. In cultured cells, acute hypoxia induced both HIF-proteins. At prolonged hypoxia, HIF-2 remained accumulated, whereas HIF-1 protein levels decreased, in agreement with the oxygen level and time-dependent induction of HIFs recently reported in neuroblastoma. [Cancer Res 2008;68(22):9212–20]

This article has been cited by other articles:

				R. Noguera, E. Fredlund, M. Piqueras, A. Pietras, S. Beckman, S. Navarro, and S. Pahlman HIF-1{alpha} and HIF-2{alpha} Are Differentially Regulated In vivo in Neuroblastoma: High HIF-1{alpha} Correlates Negatively to Advanced Clinical Stage and Tumor Vascularization Clin. Cancer Res., December 1, 2009; 15(23): 7130 - 7136. [Abstract] [Full Text] [PDF]

				A. Pietras, L. M. Hansford, A. S. Johnsson, E. Bridges, J. Sjolund, D. Gisselsson, M. Rehn, S. Beckman, R. Noguera, S. Navarro, et al. HIF-2{alpha} maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells PNAS, September 29, 2009; 106(39): 16805 - 16810. [Abstract] [Full Text] [PDF]