Estrogen and hypoxia regulate estrogen receptor alpha in a synergistic manner

Hypoxia activates and degrades estrogen receptor alpha (ERα) in human breast cancer cells, which may play an important role in the development and progression of breast cancer. In this study, the synergistic effects of estrogen (E2) and hypoxia on ERα-mediated transactivation and ERα degradation were investigated. ERα-mediated transcriptional activity was synergistically increased by E2 and hypoxia, as determined by the transient expression of ERα and ER-responsive reporter plasmids in HEK 293 cells. Twenty hours of E2 and hypoxia treatment synergistically induced degradation of ERα by 95% via a proteasome-dependent pathway in MCF-7 cells. These results provide evidence that hypoxia may stimulate yet unknown factor(s), which can further stimulate ERα signal transduction pathways.