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The transcription factor GATA-1 is overexpressed in breast carcinomas and contributes to survivin upregulation via a promoter polymorphism

Oncogene volume 29, pages 2577–2584 (2010)Cite this article

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Abstract

Expression of survivin, a member of the inhibitor of apoptosis protein family, is elevated in human cancers and considered as a new therapeutic target. Mechanism upregulating survivin expression in tumour cells is poorly understood. In this study, we show that breast cancer patients harbouring a polymorphism G235A in the survivin promoter present a higher level of survivin expression. This polymorphism creates a binding site for the transcription factor GATA-1 inducing a second GATA-1-binding site in survivin promoter. At the mRNA level, GATA-1 was present in breast carcinomas and adjacent normal tissues, whereas the protein was only detected in carcinomas by western blot and immunohistochemistry. Transfection of wild-type and different constitutively active GATA-1 mutants (serine 26, 178 or 310) showed that only phospho-serine 26 GATA-1 was able to increase survivin expression. This increase was higher in G235A than in G235G cell lines. Phospho-serine 26 GATA-1 bound directly survivin promoter, with a stronger interaction in G235A than in G235G polymorphism indicating that both GATA-1-binding sites are functional. These data identify GATA-1 as a key feature in tumour aggressiveness by enhancing survivin expression and delineate its targeting as a possible new therapeutic strategy in breast carcinomas.

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References

  • Altieri DC . (2003). Survivin in apoptosis control and cell cycle regulation in cancer. Prog Cell Cycle Res 5: 447–452.

    PubMed  Google Scholar 

  • Altieri DC . (2005). T cell expansion: the survivin interface between cell proliferation and cell death. Immunity 22: 534–535.

    Article  CAS  PubMed  Google Scholar 

  • Altieri DC . (2008). Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer 8: 61–70.

    Article  CAS  PubMed  Google Scholar 

  • Altieri DC, Marchisio PC . (1999). Survivin apoptosis:an interloper between cell death and cell proliferation in cancer. Lab Invest 11: 1327–1333.

    Google Scholar 

  • Ambrosini G, Adida C, Altieri DC . (1997). A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 3: 917–921.

    Article  CAS  PubMed  Google Scholar 

  • Boidot R, Végran F, Jacob D, Chevrier S, Gangneux N, Taboureau J et al. (2008). The expression of BIRC5 is correlated with loss of specific chromosomal regions in breast carcinomas. Genes Chromosomes Cancer 47: 299–308.

    Article  CAS  PubMed  Google Scholar 

  • Boidot R, Végran F, Lizard-Nacol S . (2009). Predictive value of survivin alternative transcript expression in locally advanced breast cancer patients treated with neoadjuvant chemotherapy. Int J Mol Med 23: 285–291.

    CAS  PubMed  Google Scholar 

  • Chiba T, Ikawa Y, Todokoro K . (1991). GATA-1 transactivates erythropoietin receptor gene, and erythropoietin receptor-mediated signals enhance GATA-1 gene expression. Nucleic Acids Res 19: 3843–3848.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ciocca DR, Calderwood SK . (2005). Heat shock proteins in cancer:diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 10: 86–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Connell CM, Wheatley SP, McNeish IA . (2008). Nuclear surviving abrogates multiple cell cycle checkpoints and enhances viral oncolysis. Cancer Res 68: 7923–7931.

    Article  CAS  PubMed  Google Scholar 

  • Crossley M, Orkin SH . (1994). Phosphorylation of the erythroid transcription factor GATA-1. J Biol Chem 269: 16589–16596.

    CAS  PubMed  Google Scholar 

  • De Gobbi M, Viprakasit V, Hughes JR, Fisher C, Buckle VJ, Ayyub H et al. (2006). A regulatory SNP causes a human genetic disease by creating a new transcriptional promoter. Science 26: 1215–1217.

    Article  Google Scholar 

  • De Maria R, Zeuner A, Eramo A, Domenichelli C, Bonci D, Grignani F et al. (1999). Negative regulation of erythropoiesis by caspase- mediated cleavage of GATA-1. Nature 401: 489–493.

    Article  CAS  PubMed  Google Scholar 

  • Gregory RC, Taxman DJ, Seshasayee D, Kensinger MH, Bieker JJ, Wojchowski DM . (1996). Functional interaction of GATA1 with erythroid Kruppel-like factor and Sp1 at defined erythroid promoters. Blood 87: 1793–1801.

    CAS  PubMed  Google Scholar 

  • Kadri Z, Maouche-Chretien L, Rooke HM, Orkin SH, Romeo PH, Mayeux P et al. (2005). Phosphatidylinositol 3-kinase/Akt induced by erythropoietin renders the erythroid differentiation factor GATA-1 competent for TIMP-1 gene transactivation. Mol Cell Biol 25: 7412–7422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leung CG, Xu Y, Mularski B, Liu H, Gurbuxani S, Crispino JD . (2007). Requirements for survivin in terminal differentiation of erythroid cells and maintenance of hematopoietic stem and progenitor cells. J Exp Med 204: 1603–1611.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li F . (2003). Survivin study:what is the next wave? J Cell Physiol 197: 8–29.

    Article  CAS  PubMed  Google Scholar 

  • Li F, Altieri DC . (1999). The cancer antiapoptosis mouse survivin gene:characterization of locus and transcriptional requirements of basal and cell cycle-dependent expression. Cancer Res 59: 3143–3151.

    CAS  PubMed  Google Scholar 

  • Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC et al. (1998). Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 396: 580–584.

    Article  CAS  PubMed  Google Scholar 

  • Nasu S, Yagihashi A, Izawa A, Saito K, Asanuma K, Nakamura M et al. (2002). Survivin mRNA expression in patients with breast cancer. Anticancer Res 3: 1839–1843.

    Google Scholar 

  • O'Driscoll L, Linehan R, Clynes M . (2003). Survivin:role in normal and in pathological conditions. Curr Cancer Drug Targets 2: 131–152.

    Article  Google Scholar 

  • Obexer P, Hagenbuchner J, Unterkircher T, Sachsenmaier N, Seifarth C, Böck G et al. (2009). Repression of BIRC5/Survivin by FOXO/FKHRL1 sensitizes human neuroblastoma cells to DNA-damage-induced apoptosis. Mol Biol Cell 20: 2041–2048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perez-Stable CM, Pozas A, Roos BA et al. (2000). A role for GATA transcription factors in the androgen regulation of the prostate-specific antigen gene enhancer. Mol Cell Endocrinol 167: 225–236.

    Article  Google Scholar 

  • Phillips TM, Kim K, Vlashi E, McBride WH, Pajonk F . (2007). Effects of recombinant erythropoietin on breast cancer-initiating cells. Neoplasia 9: 1122–1129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ribeil JA, Zermati Y, Vandekerckhove J, Cathelin S, Kersual J, Dussiot M et al. (2007). Hsp70 regulates erythropoiesis by preventing caspase-3-mediated cleavage of GATA-1. Nature 445: 102–105.

    Article  CAS  PubMed  Google Scholar 

  • Richter M, Cantin AM, Beaulieu C, Cloutier A, Larivee P . (2003). Zinc chelators inhibit eotaxin, RANTES, and MCP-1 production in stimulated human airway epithelium and fibroblasts. Am J Physiol Lung Cell Mol Physiol 285: 719–729.

    Article  Google Scholar 

  • Ryan B, O'Donovan N, Browne B, O'Shea C, Crown J, Hill AD et al. (2005). Expression of surviving and its splice variants surviving-2B and surviving-DeltaEx3 in breast cancer. Br J Cancer 92: 120–124.

    Article  CAS  PubMed  Google Scholar 

  • Sebastian S, Takayama K, Shozu M, Bulun SE . (2002). Cloning and characterization of a novel endothelial promoter of the human CYP19 (aromatase P450) gene that is up-regulated in breast cancer tissue. Mol Endocrinol 16: 2243–2254.

    Article  CAS  PubMed  Google Scholar 

  • Towatari M, Ciro M, Ottolenghi S, Tsuzuki S, Enver T . (2004). Involvement of mitogen-activated protein kinase in the cytokine-regulated phosphorylation of transcription factor GATA-1. Hematol J 5: 262–272.

    Article  CAS  PubMed  Google Scholar 

  • Végran F, Boidot R, Oudin C, Rebucci M, Riedinger JM, Lizard-Nacol S . (2007). Association of p53 gene alterations with the expression of antiapoptotic survivin splice variants in breast cancer. Oncogene 26: 290–297.

    Article  PubMed  Google Scholar 

  • Végran F, Boidot R, Oudin C, Riedinger JM, Lizard-Nacol S . (2005). Distinct expression of Survivin splice variants in breast carcinomas. Int J Oncol 27: 1151–1157.

    PubMed  Google Scholar 

  • Wu YH, You Y, Chen ZC, Zou P . (2008). Reversal of drug resistance by silencing Survivn gene expression in acute myeloid leukemia cells. Acta Biochim Pol 55: 673–680.

    CAS  PubMed  Google Scholar 

  • Xia F, Altieri DC . (2006). Mitosis-independent survivin gene expression in vivo and regulation by p53. Cancer Res 66: 3392–3395.

    Article  CAS  PubMed  Google Scholar 

  • Xu Y, Fang F, Ludewig G, Jones G, Jones D . (2004). A mutation found in the promoter region of the human survivin gene is correlated to overexpression of survivin in cancer cells. DNA Cell Biol 23: 527–537.

    Article  CAS  PubMed  Google Scholar 

  • Yu YL, Chiang YJ, Chen YC, Papetti M, Juo CG, Skoultchi AI et al. (2005). MAPK-mediated phosphorylation of GATA-1 promotes Bcl-XL expression and cell survival. J Biol Chem 280: 29533–29542.

    Article  CAS  PubMed  Google Scholar 

  • Zhao W, Kitidis C, Fleming MD, Lodish HF, Ghaffari S . (2006). Erythropoietin stimulates phosphorylation and activation of GATA-1 via the PI3-kinase/AKT signaling pathway. Blood 107: 907–915.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhen HN, Li LW, Zhang W, Fei Z, Shi CH, Yang TT et al. (2007). Short hairpin RNA targeting surviving inhibits growth and angiogenesis of glioma U251 cells. Int J Oncol 31: 1111–1117.

    CAS  PubMed  Google Scholar 

  • Zon LI, Youssoufian H, Mather C, Lodish HF, Orkin SH . (1991). Activation of the erythropoietin receptor promoter by transcription factor GATA-1. Proc Natl Acad Sci USA 88: 10638–10641.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the Conseil Regional de Bourgogne and the Association pour la Recherche contre le Cancer. We thank Dr Laurent Arnould (as Pathologist) for the validation of GATA-1 immunohistochemical staining.

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Author notes

  1. R Boidot, F Végran & O Feron

    Present address: 3Current address: Unit of Pharmacology and Therapeutics, Angiogenesis and Cancer Research Group, University of Louvain Medical School, Avenue E Mounier, 52, UCL-FATH 5349 B-1200 Brussels, Belgium.,

  2. R Boidot and F Végran: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre Georges-François Leclerc, Molecular Genetics Laboratory, Dijon, France

    R Boidot, F Végran, D Jacob, S Chevrier, M Cadouot & S Lizard-Nacol

  2. UMR-INSERM U866, IFR-100, Dijon, France

    E Solary

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  1. R Boidot
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Correspondence to S Lizard-Nacol.

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Boidot, R., Végran, F., Jacob, D. et al. The transcription factor GATA-1 is overexpressed in breast carcinomas and contributes to survivin upregulation via a promoter polymorphism. Oncogene 29, 2577–2584 (2010). https://doi.org/10.1038/onc.2009.525

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