Cobalt Chloride-Induced Estrogen Receptor α Down-Regulation Involves Hypoxia-Inducible Factor-1α in MCF-7 Human Breast Cancer Cells

Abstract

Abstract The estrogen receptor (ER) is down-regulated under hypoxia via a proteasome-dependent pathway. We studied the mechanism of ERα degradation under hypoxic mimetic conditions. Cobalt chloride-induced ERα down-regulation was dependent on the expression of newly synthesized protein(s), one possibility of which was hypoxia-inducible factor-1α (HIF-1α). To examine the role of HIF-1α expression in ERα down-regulation under hypoxic-mimetic conditions, we used a constitutively active form of HIF-1α, HIF-1α/herpes simplex viral protein 16 (VP16), constructed by replacing the transactivation domain of HIF-1α with that of VP16. Western blot analysis revealed that HIF-1α/VP16 down-regulated ERα in a dose-dependent manner via a proteasome-dependent pathway. The kinase pathway inhibitors PD98059, U0126, wortmannin, and SB203580 did not affect the down-regulation. A mammalian two-hybrid screen and immunoprecipitation assays indicated that ERα interacted with HIF-1α physically. These results suggest that ERα down-regulation under hypoxia involves protein-protein interactions between the ERα and HIF-1α.