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Hypoxia Down-regulates CCAAT/Enhancer Binding Protein- Expression in Breast Cancer Cells

¹ INSERM U612; ² Institut Curie, Orsay, France; ³ INSERM U747; ⁴ Université Paris Descartes; ⁵ Service d'Anatomo-Pathologie, ⁶ Service de Gynécologie Chirurgicale, and ⁷ Laboratoire de Biochimie, Hôpital Européen Georges Pompidou, AP-HP; ⁸ CNRS, UPR 2226, Paris, France; and ⁹ CNRS, UMR 6543, Centre Antoine Lacassagne, Nice, France

Requests for reprints: Liliane Massade, UMR 8121 CNRS and Institut de Formation Supérieure Biomédicale, PR2, 39 rue Camille Desmoulins, 94805 Villejuif, France. Phone: 33-1-42-11-62-42; E-mail: liliane.massade{at}igr.fr.

Key Words: Hypoxia • C/EBP • HIF-1 • breast cancer cell lines

The transcription factor CCAAT/enhancer binding protein- (C/EBP) is involved in the control of cell differentiation and proliferation, and has been suggested to act as a tumor suppressor in several cancers. By using microarray analysis, we have previously shown that hypoxia and estrogen down-regulate C/EBP mRNA in T-47D breast cancer cells. Here, we have examined the mechanism by which the down-regulation by hypoxia takes place. Using the specific RNA polymerase II inhibitor 5,6-dichlorobenzimidazole-1-β-D-ribofuranoside, the mRNA stability was analyzed under normoxia or hypoxia by quantitative reverse transcription-PCR. Hypoxia reduced the half-life of C/EBP mRNA by 30%. C/EBP gene promoter studies indicated that hypoxia also repressed the transcription of the gene and identified a hypoxia-responsive element (–522; –527 bp), which binds to hypoxia-inducible factor (HIF)-1, as essential for down-regulation of C/EBP transcription in hypoxia. Immunocytochemical analysis showed that C/EBP was localized in the nucleus at 21% O₂, but was mostly cytoplasmic under 1% O₂. Knockdown of HIF-1 by RNAi restored C/EBP to normal levels under hypoxic conditions. Immunohistochemical studies of 10 tumor samples did not show any colocalization of C/EBP and glucose transporter 1 (used as a marker for hypoxia). Taken together, these results show that hypoxia down-regulates C/EBP expression in breast cancer cells by several mechanisms, including transcriptional and posttranscriptional effects. The down-regulation of C/EBP in hypoxia is mediated by HIF-1. [Cancer Res 2008;68(7):2158–65]

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