Hypoxia induces proteasome-dependent degradation of estrogen receptor alpha in ZR-75 breast cancer cells.
Regulation of estrogen receptor alpha (ERalpha) 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% O(2)) or hypoxia (1% O(2) or cobaltous chloride), and hypoxia significantly increased hypoxia-inducible factor 1alpha protein within 3 h after treatment, whereas ERalpha 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 ERalpha mRNA; however, hypoxic conditions decreased basal and 17beta-estradiol-induced pS2 gene expression (mRNA levels) and estrogen response element-dependent reporter gene activity in ZR-75 cells. Although 17beta-estradiol and hypoxia induce proteasome-dependent degradation of ERalpha, their effects on transactivation are different, and this may have implications for clinical treatment of mammary tumors.
D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D015687:Cell Hypoxia; D003035:Cobalt / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D016228:Endothelial Growth Factors / Q000235:genetics; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007976:Leupeptins / Q000494:pharmacology; D008222:Lymphokines / Q000235:genetics; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000187:drug effects / Q000235:genetics; D011960:Receptors, Estrogen / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000187:drug effects / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D000071163:Trefoil Factor-1; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D047628:Estrogen Receptor alpha; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D007976:Leupeptins; D008222:Lymphokines; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D011506:Proteins; D011960:Receptors, Estrogen; D016329:Sp1 Transcription Factor; C051838:TFF1 protein, human; D014157:Transcription Factors; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D003035:Cobalt; D004958:Estradiol; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C018021:cobaltous chloride; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde