Hypoxia induces proteasome-dependent degradation of estrogen receptor α in ZR-75 breast cancer cells

Regulation of estrogen receptor α (ERα) plays an important role in hormone responsiveness and growth of ER-positive breast cancer cells and tumors. ZR-75 breast cancer cells were grown under conditions of normoxia (21% O₂) or hypoxia (1% O₂ or cobaltous chloride), and hypoxia significantly increased hypoxia-inducible factor 1α protein within 3 h after treatment, whereas ERα protein levels were dramatically decreased within 6-12 h, and this response was blocked by the proteasome inhibitor MG-132. In contrast, hypoxia induced only minimal decreases in cellular Sp1 protein and did not affect ERα mRNA; however, hypoxic conditions decreased basal and 17βestradiol-induced pS2 gene expression (mRNA levels) and estrogen response element-dependent reporter gene activity in ZR-75 cells. Although 17β-estradiol and hypoxia induce proteasome-dependent degradation of ERα, their effects on transactivation are different, and this may have implications for clinical treatment of mammary tumors.