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Tumor Biology |
and HIF-2 Expression to Vascular Endothelial Growth Factor Induction and Hypoxia Survival in Human Breast Cancer Cell Lines
Imperial Cancer Research Fund, Molecular Oncology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom
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-1
and HIF-2 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-1 at various levels, but HIF-2 was low or absent from the
more aggressive cell lines. There was an inverse correlation between
HIF-1 and HIF-2 induction and clonogenic survival under hypoxia.
Thus, cell lines with reduced induction of HIF-1 or HIF-2 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-2
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-2 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.
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