Hypoxic activation of unoccupied estrogen-receptor-alpha is mediated by hypoxia-inducible factor-1 alpha

The estrogen receptor (ER) plays an important role in breast cancer development and progression. Hypoxia has been shown to modulate the level of ERα expression, which is intimately associated with the biology of breast carcinomas. However, the effect of hypoxia on ERα-mediated transactivation is largely unknown. In this report, we have examined ligand-independent transcriptional activation of ERα by hypoxia. The hypoxia-induced ERα-mediated transcriptional response was inhibited by the ER antagonist ICI 182,780 as determined by transient expression of ERα and ER-responsive reporter plasmids in the HEK 293 cells. Hypoxic activation of ERα was dependent on the increased expression of hypoxia-inducible factor-1α (HIF-1α), as examined in HEK 293 cells under conditions of normoxia. These results indicate that hypoxia activates ERα in a ligand-independent manner, possibly through the interaction between HIF-1α and ERα.