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Hypoxia-inducible factors (HIF-1 and HIF-2) are two closely related protein complexes that activate transcription of target genes in response to hypoxia. Expression of HIF-1alpha and HIF-2alpha and their effects on survival under hypoxia were studied in six human breast cancer cell lines. We also evaluated the basal and inducible expression of two hypoxically regulated genes, vascular endothelial growth factor (VEGF) and lactate dehydrogenase-A (LDH-A). All of the cell lines studied expressed HIF-1alpha at various levels, but HIF-2alpha was low or absent from the more aggressive cell lines. There was an inverse correlation between HIF-1alpha and HIF-2alpha induction and clonogenic survival under hypoxia. Thus, cell lines with reduced induction of HIF-1alpha or HIF-2alpha showed high basal levels of VEGF and improved survival under hypoxia. A reduction in HIF expression was also associated with a more aggressive phenotype in vivo. To confirm these results, we carried out stable transfection of the MDA 435 cell line with human HIF-2alpha cDNA. There was no change in the growth rate in monolayer culture. However, in vitro growth as colonies and in vivo tumor growth of the HIF-2alpha overexpressing cells were significantly impaired compared with the control transfectants. Thus, despite the fact that HIF proteins are necessary for optimal tumor growth and angiogenesis in vivo, overexpression of these molecules seems detrimental to tumor growth. A balance between the angiogenic and tumor-inhibiting levels of HIF proteins may, therefore, be necessary for optimal tumor growth.

Type

Journal article

Journal

Cancer Res

Publication Date

15/12/2000

Volume

60

Pages

7106 - 7113

Keywords

Animals, Basic Helix-Loop-Helix Transcription Factors, Blotting, Western, Breast Neoplasms, Cell Survival, Cells, Cultured, DNA, Complementary, DNA-Binding Proteins, Endothelial Growth Factors, Humans, Hypoxia, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoblotting, Isoenzymes, L-Lactate Dehydrogenase, Lymphokines, Mice, Mice, Nude, Neoplasm Transplantation, Neovascularization, Pathologic, Nuclear Proteins, Phenotype, RNA, Trans-Activators, Transcription Factors, Transcription, Genetic, Transfection, Tumor Cells, Cultured, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors