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Breast Cancer Research and Treatment

, Volume 121, Issue 1, pp 185–194 | Cite as

Polymorphisms in the UBC9 and PIAS3 genes of the SUMO-conjugating system and breast cancer risk

  • Thomas Dünnebier
  • Justo Lorenzo Bermejo
  • Susanne Haas
  • Hans-Peter Fischer
  • Christiane B. Pierl
  • Christina Justenhoven
  • Hiltrud Brauch
  • Christian Baisch
  • Michael Gilbert
  • Volker Harth
  • Anne Spickenheuer
  • Sylvia Rabstein
  • Beate Pesch
  • Thomas Brüning
  • Yon-Dschun Ko
  • Ute Hamann
Epidemiology

Abstract

SUMOylation consists in the covalent conjugation of small ubiquitin-related modifiers to target proteins. SUMOylation participates in processes that are tightly linked to tumorigenesis, and genetic variability in the SUMO-conjugating system may influence the development of breast cancer. We recently reported that variation in the UBC9 gene encoding the SUMO-conjugating enzyme may affect the grade of breast tumors. Following comprehensive in silico analyses for detection of putative functional polymorphisms in 14 genes of the SUMO system, we selected one coding SNP in PIAS3 and seven tag SNPs in UBC9 for association analyses. Results were based on 1,021 cases, and 1,015 matched controls from the population-based GENICA study. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by conditional logistic regression. To explore the association with polymorphisms closely linked to the genotyped variants, multiple imputation based on HapMap data was applied. The study revealed associations of four UBC9 polymorphisms with risk of grade 1 tumors. Comparison of genotype and haplotype models indicated that the best representation of risk solely relied on rs7187167 under dominant penetrance. Women carrying the rare allele showed an increased risk of grade 1 tumors compared with common homozygotes (OR 1.87, 95% CI 1.18–2.95). This effect appeared to be stronger in women with a family history of breast or ovarian cancer. Imputation of polymorphisms in a 300-kb region around the genotyped polymorphisms identified no variants with stronger associations. Our findings suggest that genetic variation in UBC9 may affect the risk of grade 1 breast tumors.

Keywords

UBC9 and PIAS3 polymorphisms SUMOylation Breast cancer risk Tumor grade Multiple imputation 

Notes

Acknowledgments

We are indebted to all women participating in the GENICA study. We gratefully acknowledge support by interviewers as well as physicians and pathologists of the study region. We thank Axel Benner for his contribution to the statistical analysis and Agnes Hotz-Wagenblatt as well as Karl-Heinz Glatting for their support in using the software PromoterSweep. Further gratitude goes to Antje Seidel-Renkert for expert technical assistance. This work was supported by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9976/8, 01KW9975/5, 01KW9977/0 and 01KW0114, the Deutsches Krebsforschungszentrum, Heidelberg, the Robert Bosch Foundation of Medical Research, Stuttgart, BGFA-Forschungsinstitut für Arbeitsmedizin der Deutschen Gesetzlichen Unfallversicherung, Bochum, and the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany.

Competing interests

The authors declare that they have no competing interests.

Supplementary material

References

  1. 1.
    Geiss-Friedlander R, Melchior F (2007) Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol 8:947–956CrossRefPubMedGoogle Scholar
  2. 2.
    Muller S, Hoege C, Pyrowolakis G, Jentsch S (2001) SUMO, ubiquitin’s mysterious cousin. Nat Rev Mol Cell Biol 2:202–210CrossRefPubMedGoogle Scholar
  3. 3.
    Dasso M (2008) Emerging roles of the SUMO pathway in mitosis. Cell Div 3:5CrossRefPubMedGoogle Scholar
  4. 4.
    Hay RT (2005) SUMO: a history of modification. Mol Cell 18:1–12CrossRefPubMedGoogle Scholar
  5. 5.
    Seeler JS, Bischof O, Nacerddine K, Dejean A (2007) SUMO, the three Rs and cancer. Curr Top Microbiol Immunol 313:49–71CrossRefPubMedGoogle Scholar
  6. 6.
    Gostissa M, Hengstermann A, Fogal V, Sandy P, Schwarz SE, Scheffner M, Del Sal G (1999) Activation of p53 by conjugation to the ubiquitin-like protein SUMO-1. EMBO J 18:6462–6471CrossRefPubMedGoogle Scholar
  7. 7.
    Muller S, Berger M, Lehembre F, Seeler JS, Haupt Y, Dejean A (2000) c-Jun and p53 activity is modulated by SUMO-1 modification. J Biol Chem 275:13321–13329CrossRefPubMedGoogle Scholar
  8. 8.
    Muller S, Matunis MJ, Dejean A (1998) Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus. EMBO J 17:61–70CrossRefPubMedGoogle Scholar
  9. 9.
    Rodriguez MS, Desterro JM, Lain S, Midgley CA, Lane DP, Hay RT (1999) SUMO-1 modification activates the transcriptional response of p53. EMBO J 18:6455–6461CrossRefPubMedGoogle Scholar
  10. 10.
    Eladad S, Ye TZ, Hu P, Leversha M, Beresten S, Matunis MJ, Ellis NA (2005) Intra-nuclear trafficking of the BLM helicase to DNA damage-induced foci is regulated by SUMO modification. Hum Mol Genet 14:1351–1365CrossRefPubMedGoogle Scholar
  11. 11.
    Kawabe Y, Seki M, Seki T, Wang WS, Imamura O, Furuichi Y, Saitoh H, Enomoto T (2000) Covalent modification of the Werner’s syndrome gene product with the ubiquitin-related protein, SUMO-1. J Biol Chem 275:20963–20966CrossRefPubMedGoogle Scholar
  12. 12.
    Bossis G, Malnou CE, Farras R, Andermarcher E, Hipskind R, Rodriguez M, Schmidt D, Muller S, Jariel-Encontre I, Piechaczyk M (2005) Down-regulation of c-Fos/c-Jun AP-1 dimer activity by sumoylation. Mol Cell Biol 25:6964–6979CrossRefPubMedGoogle Scholar
  13. 13.
    Xirodimas DP, Chisholm J, Desterro JM, Lane DP, Hay RT (2002) P14ARF promotes accumulation of SUMO-1 conjugated (H)Mdm2. FEBS Lett 528:207–211CrossRefPubMedGoogle Scholar
  14. 14.
    Mo YY, Yu Y, Theodosiou E, Rachel Ee PL, Beck WT (2005) A role for Ubc9 in tumorigenesis. Oncogene 24:2677–2683CrossRefPubMedGoogle Scholar
  15. 15.
    Cheng J, Bawa T, Lee P, Gong L, Yeh ET (2006) Role of desumoylation in the development of prostate cancer. Neoplasia 8:667–676CrossRefPubMedGoogle Scholar
  16. 16.
    Wang L, Banerjee S (2004) Differential PIAS3 expression in human malignancy. Oncol Rep 11:1319–1324PubMedGoogle Scholar
  17. 17.
    Moschos SJ, Smith AP, Mandic M, Athanassiou C, Watson-Hurst K, Jukic DM, Edington HD, Kirkwood JM, Becker D (2007) SAGE and antibody array analysis of melanoma-infiltrated lymph nodes: identification of Ubc9 as an important molecule in advanced-stage melanomas. Oncogene 26:4216–4225CrossRefPubMedGoogle Scholar
  18. 18.
    Wu F, Zhu S, Ding Y, Beck WT, Mo YY (2009) MicroRNA-mediated regulation of Ubc9 expression in cancer cells. Clin Cancer Res 15:1550–1557CrossRefPubMedGoogle Scholar
  19. 19.
    Karamouzis MV, Konstantinopoulos PA, Badra FA, Papavassiliou AG (2008) SUMO and estrogen receptors in breast cancer. Breast Cancer Res Treat 107:195–210CrossRefPubMedGoogle Scholar
  20. 20.
    Ali S, Coombes RC (2000) Estrogen receptor alpha in human breast cancer: occurrence and significance. J Mammary Gland Biol Neoplasia 5:271–281CrossRefPubMedGoogle Scholar
  21. 21.
    Sentis S, Le Romancer M, Bianchin C, Rostan MC, Corbo L (2005) Sumoylation of the estrogen receptor alpha hinge region regulates its transcriptional activity. Mol Endocrinol 19:2671–2684CrossRefPubMedGoogle Scholar
  22. 22.
    Chauchereau A, Amazit L, Quesne M, Guiochon-Mantel A, Milgrom E (2003) Sumoylation of the progesterone receptor and of the steroid receptor coactivator SRC-1. J Biol Chem 278:12335–12343CrossRefPubMedGoogle Scholar
  23. 23.
    Kotaja N, Karvonen U, Janne OA, Palvimo JJ (2002) The nuclear receptor interaction domain of GRIP1 is modulated by covalent attachment of SUMO-1. J Biol Chem 277:30283–30288CrossRefPubMedGoogle Scholar
  24. 24.
    Wu H, Sun L, Zhang Y, Chen Y, Shi B, Li R, Wang Y, Liang J, Fan D, Wu G et al (2006) Coordinated regulation of AIB1 transcriptional activity by sumoylation and phosphorylation. J Biol Chem 281:21848–21856CrossRefPubMedGoogle Scholar
  25. 25.
    Dunnebier T, Bermejo JL, Haas S, Fischer HP, Pierl CB, Justenhoven C, Brauch H, Baisch C, Gilbert M, Harth V et al (2009) Common variants in the UBC9 gene encoding the SUMO-conjugating enzyme are associated with breast tumor grade. Int J Cancer 125:596–602CrossRefPubMedGoogle Scholar
  26. 26.
    Pesch B, Ko Y, Brauch H, Hamann U, Harth V, Rabstein S, Pierl C, Fischer HP, Baisch C, Justenhoven C et al (2005) Factors modifying the association between hormone-replacement therapy and breast cancer risk. Eur J Epidemiol 20:699–711CrossRefPubMedGoogle Scholar
  27. 27.
    Justenhoven C, Hamann U, Pesch B, Harth V, Rabstein S, Baisch C, Vollmert C, Illig T, Ko YD, Bruning T et al (2004) ERCC2 genotypes and a corresponding haplotype are linked with breast cancer risk in a German population. Cancer Epidemiol Biomarkers Prev 13:2059–2064PubMedGoogle Scholar
  28. 28.
    Justenhoven C, Pierl CB, Haas S, Fischer HP, Baisch C, Hamann U, Harth V, Pesch B, Bruning T, Vollmert C et al (2008) The CYP1B1_1358_GG genotype is associated with estrogen receptor-negative breast cancer. Breast Cancer Res Treat 111:171–177CrossRefPubMedGoogle Scholar
  29. 29.
    del Val C, Pelz O, Glatting K-H, Barta E, Hotz-Wagenblatt A (2009) PromoterSweep: a tool for identification of transcription factor binding sites. Theor Chem Acc (in press)Google Scholar
  30. 30.
    Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, Gibbs RA, Belmont JW, Boudreau A, Hardenbol P, Leal SM et al (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449:851–861CrossRefPubMedGoogle Scholar
  31. 31.
    Ramensky V, Bork P, Sunyaev S (2002) Human non-synonymous SNPs: server and survey. Nucleic Acids Res 30:3894–3900CrossRefPubMedGoogle Scholar
  32. 32.
    Thomas PD, Campbell MJ, Kejariwal A, Mi H, Karlak B, Daverman R, Diemer K, Muruganujan A, Narechania A (2003) PANTHER: a library of protein families and subfamilies indexed by function. Genome Res 13:2129–2141CrossRefPubMedGoogle Scholar
  33. 33.
    Thomas PD, Kejariwal A, Guo N, Mi H, Campbell MJ, Muruganujan A, Lazareva-Ulitsky B (2006) Applications for protein sequence-function evolution data: mRNA/protein expression analysis and coding SNP scoring tools. Nucleic Acids Res 34(Web Server issue):W645–650Google Scholar
  34. 34.
    Westfall PH, Young SS (1993) Resampling-Based Multiple Testing. Wiley, New YorkGoogle Scholar
  35. 35.
    Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA (2002) Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 70:425–434CrossRefPubMedGoogle Scholar
  36. 36.
    Marchini J, Howie B, Myers S, McVean G, Donnelly P (2007) A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet 39:906–913CrossRefPubMedGoogle Scholar
  37. 37.
    Antoniou AC, Easton DF (2003) Polygenic inheritance of breast cancer: implications for design of association studies. Genet Epidemiol 25:190–202CrossRefPubMedGoogle Scholar
  38. 38.
    Daniels RJ, Peden JF, Lloyd C, Horsley SW, Clark K, Tufarelli C, Kearney L, Buckle VJ, Doggett NA, Flint J et al (2001) Sequence, structure and pathology of the fully annotated terminal 2 Mb of the short arm of human chromosome 16. Hum Mol Genet 10:339–352CrossRefPubMedGoogle Scholar
  39. 39.
    Zhao J (2007) Sumoylation regulates diverse biological processes. Cell Mol Life Sci 64:3017–3033CrossRefPubMedGoogle Scholar
  40. 40.
    Shen Q, Uray IP, Li Y, Krisko TI, Strecker TE, Kim HT, Brown PH (2008) The AP-1 transcription factor regulates breast cancer cell growth via cyclins and E2F factors. Oncogene 27:366–377CrossRefPubMedGoogle Scholar
  41. 41.
    Vousden KH, Lane DP (2007) p53 in health and disease. Nat Rev Mol Cell Biol 8:275–283CrossRefPubMedGoogle Scholar
  42. 42.
    Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408:307–310CrossRefPubMedGoogle Scholar
  43. 43.
    Chen GG, Zeng Q, Tse GM (2008) Estrogen and its receptors in cancer. Med Res Rev 28:954–974CrossRefPubMedGoogle Scholar
  44. 44.
    Yang W, Paschen W (2009) Gene expression and cell growth are modified by silencing SUMO2 and SUMO3 expression. Biochem Biophys Res Commun 382:215–218CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Thomas Dünnebier
    • 1
  • Justo Lorenzo Bermejo
    • 2
  • Susanne Haas
    • 3
  • Hans-Peter Fischer
    • 3
  • Christiane B. Pierl
    • 4
  • Christina Justenhoven
    • 5
    • 6
  • Hiltrud Brauch
    • 5
    • 6
  • Christian Baisch
    • 7
  • Michael Gilbert
    • 1
  • Volker Harth
    • 4
    • 7
  • Anne Spickenheuer
    • 4
  • Sylvia Rabstein
    • 4
  • Beate Pesch
    • 4
  • Thomas Brüning
    • 4
  • Yon-Dschun Ko
    • 7
  • Ute Hamann
    • 1
  1. 1.Molecular Genetics of Breast Cancer (B055)Deutsches KrebsforschungszentrumHeidelbergGermany
  2. 2.Institute of Medical Biometry and InformaticsUniversity Hospital HeidelbergHeidelbergGermany
  3. 3.Institute of PathologyMedical Faculty of the University of BonnBonnGermany
  4. 4.BGFA-Forschungsinstitut für Arbeitsmedizin der Deutschen Gesetzlichen UnfallversicherungRuhr University BochumBochumGermany
  5. 5.Dr. Margarete Fischer-Bosch-Institute of Clinical PharmacologyStuttgartGermany
  6. 6.University of TübingenTübingenGermany
  7. 7.Department of Internal MedicineEvangelische Kliniken Bonn gGmbH, Johanniter KrankenhausBonnGermany

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