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

Karolina Helczynska, Anna Maria Larsson, Linda Holmquist Mengelbier, Esther Bridges, 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)-α subunits HIF-1α and HIF-2α in various tumors and cell lines have been suggested. In breast cancer, the prognostic significance of HIF-1α is not clear-cut and that of HIF-2α is largely unknown. Using IHC analyses of HIF-1α, HIF-2α, 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-α subunits in relation to established clinicopathologic variables, VEGF expression, and survival. HIF-1α and HIF-2α 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-α protein and HIF-α and VEGF mRNA levels were further studied in cultured breast cancer cells after hypoxic induction and/or knockdown of HIF-α subunits by siRNA by Western blot and Quantitative Real-Time PCR techniques. We showed that although HIF-1α and HIF-2α protein levels in breast cancer specimens were not interrelated, high levels of both HIF-1α and HIF-2α associated to high VEGF expression. HIF-2α expression was an independent prognostic factor associated to reduced recurrence-free and breast cancer-specific survival, whereas HIF-1α did not exhibit these correlations. In cultured cells, acute hypoxia induced both HIF-proteins. At prolonged hypoxia, HIF-2α remained accumulated, whereas HIF-1α protein levels decreased, in agreement with the oxygen level and time-dependent induction of HIFs recently reported in neuroblastoma. ©2008 American Association for Cancer Research.
    Original languageEnglish
    Pages (from-to)9212-9220
    Number of pages8
    JournalCancer Research
    Volume68
    Issue number22
    DOIs
    Publication statusPublished - 15 Nov 2008

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