Hypoxia activates and degrades estrogen receptor alpha (ER.) 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 (E-2) and hypoxia on ER alpha-mediated transactivation and ER alpha degradation were investigated. ER alpha-mediated transcriptional activity was synergistically increased by E-2 and hypoxia, as determined by the transient expression of ER alpha and ER-responsive reporter plasmids in HEK 293 cells. Twenty hours of E-2 and hypoxia treatment synergistically induced degradation of ER alpha 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 ER alpha signal transduction pathways. (C) 2008 Elsevier Inc. All rights reserved.