Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Breast Neoplasms / drug therapy
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Cell Division / drug effects
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Cell Hypoxia
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Cobalt / pharmacology
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Cysteine Endopeptidases / metabolism*
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Endothelial Growth Factors / genetics
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Estradiol / pharmacology
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Estrogen Receptor alpha
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Female
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit
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Intercellular Signaling Peptides and Proteins / genetics
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Leupeptins / pharmacology
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Lymphokines / genetics
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Multienzyme Complexes / antagonists & inhibitors
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Multienzyme Complexes / metabolism*
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Promoter Regions, Genetic
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Protease Inhibitors / pharmacology
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Proteasome Endopeptidase Complex
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Proteins / drug effects
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Proteins / genetics
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Receptors, Estrogen / drug effects
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Receptors, Estrogen / genetics
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Receptors, Estrogen / metabolism*
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Response Elements / drug effects
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Response Elements / genetics
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Sp1 Transcription Factor / drug effects
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Sp1 Transcription Factor / metabolism
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Transcription Factors / drug effects
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcriptional Activation
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Trefoil Factor-1
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Tumor Cells, Cultured
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Tumor Suppressor Proteins
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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Endothelial Growth Factors
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Estrogen Receptor alpha
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Intercellular Signaling Peptides and Proteins
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Leupeptins
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Lymphokines
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Multienzyme Complexes
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Protease Inhibitors
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Proteins
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Receptors, Estrogen
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Sp1 Transcription Factor
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TFF1 protein, human
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Transcription Factors
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Trefoil Factor-1
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Tumor Suppressor Proteins
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Cobalt
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Estradiol
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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cobaltous chloride
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde