pVHL-mediated degradation of HIF-2α regulates estrogen receptor α expression in normoxic breast cancer cells.

Estrogen receptor α (ERα) functions as a transcription factor for genes involved in estrogen-dependent development of breast cancer cells. We demonstrate here that knockdown of hypoxia-inducible factor (HIF)-2α, but not of HIF-1α, increases endogenous ERα protein expression in normoxia and hypoxia. The von Hippel-Lindau protein (pVHL)-dependent degradation of HIF-2α participates in the regulation of ERα expression. Additionally, HIF-2α forms a protein complex with ERα, and amino acids 396-823 of HIF-2α physically interact with the ligand-binding domain of ERα. These results indicate that HIF-2α functions as a negative regulator of ERα expression in breast cancer, especially in normoxia.