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SUMOylation proteins in breast cancer

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Abstract

Small Ubiquitin-like Modifier proteins (or SUMO) modify the function of protein substrates involved in various cellular processes including DNA damage response (DDR). It is becoming apparent that dysregulated SUMO contribute to carcinogenesis by affecting post-transcriptional modification of key proteins. It is hypothesised that SUMO contributes to the aggressive nature of breast cancer particularly those associated with features similar to breast carcinoma arising in patients with BRCA1 germline mutations. This study aims to assess the clinical and biological significance of three members of SUMO in a well-characterised annotated series of BC with emphasis on DDR. The study cohort comprised primary operable invasive BC including tumours from patients with known BRCA1 germline mutations. SUMO proteins PIAS1, PIAS4 and UBC9 were assessed using immunohistochemistry utilising tissue microarray technology. Additionally, their expression was assessed using reverse phase protein microarray utilising different cell lines. PIAS1 and UBC9 showed cytoplasmic and/or nuclear expression while PIAS4 was detected only in the nuclei. There was a correlation between subcellular localisation and expression of the nuclear transport protein KPNA2. Tumours showing positive nuclear/negative cytoplasmic expression of SUMO featured good prognostic characteristics including lower histologic grade and had a good outcome. Strong correlation with DDR-related proteins including BRCA1, Rad51, ATM, CHK1, DNA-PK and KU70/KU80 was observed. Correlation with ER and BRCA1 was confirmed using RPPA on cell lines. SUMO proteins seem to play important role in BC. Not only expression but also subcellular location is associated with BC phenotype.

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References

  1. Pinder JB, Attwood KM, Dellaire G (2013) Reading, writing, and repair: the role of ubiquitin and the ubiquitin-like proteins in DNA damage signaling and repair. Front Genet 4:45

    Article  PubMed Central  PubMed  Google Scholar 

  2. Bologna S, Ferrari S (2013) It takes two to tango: ubiquitin and SUMO in the DNA damage response. Front Genet 4:106

    Article  PubMed Central  PubMed  Google Scholar 

  3. Al-Hakim A et al (2010) The ubiquitous role of ubiquitin in the DNA damage response. DNA Repair (Amst) 9(12):1229–1240

    Article  CAS  Google Scholar 

  4. Matunis MJ, Coutavas E, Blobel G (1996) A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex. J Cell Biol 135(6 Pt 1):1457–1470

    Article  PubMed  CAS  Google Scholar 

  5. Mahajan R et al (1997) A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2. Cell 88(1):97–107

    Article  PubMed  CAS  Google Scholar 

  6. Morris JR (2010) More modifiers move on DNA damage. Cancer Res 70(10):3861–3863

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  7. Mo YY et al (2005) A role for Ubc9 in tumorigenesis. Oncogene 24(16):2677–2683

    Article  PubMed  CAS  Google Scholar 

  8. Moschos SJ, Mo YY (2006) Role of SUMO/Ubc9 in DNA damage repair and tumorigenesis. J Mol Histol 37(5–7):309–319

    Article  PubMed  CAS  Google Scholar 

  9. Moschos SJ et al (2010) Expression analysis of Ubc9, the single small ubiquitin-like modifier (SUMO) E2 conjugating enzyme, in normal and malignant tissues. Hum Pathol 41(9):1286–1298

    Article  PubMed  CAS  Google Scholar 

  10. Hoefer J et al (2012) PIAS1 is increased in human prostate cancer and enhances proliferation through inhibition of p21. Am J Pathol 180(5):2097–2107

    Article  PubMed  CAS  Google Scholar 

  11. Agboola A et al (2013) PIASgamma expression in relation to clinicopathological, tumour factors and survival in indigenous black breast cancer women. J Clin Pathol. doi:10.1136/jclinpath-2013-201658

    PubMed  Google Scholar 

  12. Alshareeda AT et al (2013) Clinicopathological significance of KU70/KU80, a key DNA damage repair protein in breast cancer. Breast Cancer Res Treat 139(2):301–310

    Article  PubMed  CAS  Google Scholar 

  13. Rakha EA et al (2006) Morphological and immunophenotypic analysis of breast carcinomas with basal and myoepithelial differentiation. J Pathol 208(4):495–506

    Article  PubMed  CAS  Google Scholar 

  14. Rakha EA et al (2009) Triple-negative breast cancer: distinguishing between basal and nonbasal subtypes. Clin Cancer Res 15(7):2302–2310

    Article  PubMed  CAS  Google Scholar 

  15. Alshareeda AT et al (2012) Fatty acid binding protein 7 expression and its sub-cellular localization in breast cancer. Breast Cancer Res Treat 134(2):519–529

    Article  PubMed  CAS  Google Scholar 

  16. Aleskandarany MA et al (2012) Prognostic value of proliferation assay in the luminal, HER2-positive, and triple-negative biologic classes of breast cancer. Breast Cancer Res 14(1):R3

    Article  PubMed Central  PubMed  Google Scholar 

  17. Bergink S, Jentsch S (2009) Principles of ubiquitin and SUMO modifications in DNA repair. Nature 458(7237):461–467

    Article  PubMed  CAS  Google Scholar 

  18. Sachdev S et al (2001) PIASy, a nuclear matrix-associated SUMO E3 ligase, represses LEF1 activity by sequestration into nuclear bodies. Genes Dev 15(23):3088–3103

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  19. Sentis S et al (2005) Sumoylation of the estrogen receptor alpha hinge region regulates its transcriptional activity. Mol Endocrinol 19(11):2671–2684

    Article  PubMed  CAS  Google Scholar 

  20. Morris JR et al (2009) The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress. Nature 462(7275):886–890

    Article  PubMed  CAS  Google Scholar 

  21. Qin Y et al (2011) Ubc9 mediates nuclear localization and growth suppression of BRCA1 and BRCA1a proteins. J Cell Physiol 226(12):3355–3367

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  22. Chen SF et al (2011) Ubc9 expression predicts chemoresistance in breast cancer. Chin J Cancer 30(9):638–644

    Article  PubMed  CAS  Google Scholar 

  23. Agboola AO et al (2014) Clinicopathological and molecular significance of Sumolyation marker (ubiquitin conjugating enzyme 9 (UBC9)) expression in breast cancer of black women. Pathol Res Pract 210(1):10–17

    Article  PubMed  CAS  Google Scholar 

  24. Clevenger CV (2004) Roles and regulation of stat family transcription factors in human breast cancer. Am J Pathol 165(5):1449–1460

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  25. Wei J et al (2011) mRNA expression of BRCA1, PIAS1, and PIAS4 and survival after second-line docetaxel in advanced gastric cancer. J Natl Cancer Inst 103(20):1552–1556

    Article  PubMed  CAS  Google Scholar 

  26. Coppola D et al (2009) Substantially reduced expression of PIAS1 is associated with colon cancer development. J Cancer Res Clin Oncol 135(9):1287–1291

    Article  PubMed  CAS  Google Scholar 

  27. Baek SH (2006) A novel link between SUMO modification and cancer metastasis. Cell Cycle 5(14):1492–1495

    Article  PubMed  CAS  Google Scholar 

  28. Chook Y, Blobel G (2001) Karyopherins and nuclear import. Curr Opin Struct Biol 11(6):703–715

    Article  PubMed  CAS  Google Scholar 

  29. Xu J et al (2009) A novel mechanism whereby BRCA1/1a/1b fine tunes the dynamic complex interplay between SUMO-dependent/independent activities of Ubc9 on E2-induced ERalpha activation/repression and degradation in breast cancer cells. Int J Oncol 34(4):939–949

    PubMed  CAS  Google Scholar 

  30. Martin RW et al (2007) RAD51 up-regulation bypasses BRCA1 function and is a common feature of BRCA1-deficient breast tumors. Cancer Res 67(20):9658–9665

    Article  PubMed  CAS  Google Scholar 

  31. Abdel-Fatah TM et al (2010) The biological, clinical and prognostic implications of p53 transcriptional pathways in breast cancers. J Pathol 220(4):419–434

    PubMed  CAS  Google Scholar 

  32. Aleskandarany MA et al (2011) MIB1/Ki-67 labelling index can classify grade 2 breast cancer into two clinically distinct subgroups. Breast Cancer Res Treat 127(3):591–599

    Article  PubMed  CAS  Google Scholar 

  33. Kahyo T, Nishida T, Yasuda H (2001) Involvement of PIAS1 in the sumoylation of tumor suppressor p53. Mol Cell 8(3):713–718

    Article  PubMed  CAS  Google Scholar 

  34. Park MA et al (2008) SUMO1 negatively regulates BRCA1-mediated transcription, via modulation of promoter occupancy. Nucleic Acids Res 36(1):263–283

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  35. Cortez D et al (1999) Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 286(5442):1162–1166

    Article  PubMed  CAS  Google Scholar 

  36. Mohanty S et al (2014) ROS-PIASgamma cross talk channelizes ATM signaling from resistance to apoptosis during chemosensitization of resistant tumors. Cell Death Dis 5:e1021

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Alaa Alshareeda is sponsored by the higher education of kingdom of Saudi Arabia.

Conflict of interest

None.

Funding

No financial relationship with the organisation that sponsored the research.

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Authors and Affiliations

  1. Department of Histopathology and School of Molecular Medical Sciences, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK

    Alaa T. Alshareeda, Andrew R. Green, Christopher Nolan, Ian O. Ellis & Emad A. Rakha

  2. Ministry of Higher Education, Riyadh, Saudi Arabia

    Alaa T. Alshareeda

  3. Immunology, University of Nottingham, School of Life Sciences, Nottingham, UK

    Ola H. Negm & Paddy Tighe

  4. Medical Microbiology and Immunology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt

    Ola H. Negm

  5. Department of Oncology and School of Molecular Medical Sciences, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK

    Nada Albarakati, Rebeka Sultana & Srinivasan Madhusudan

  6. Department of Histopathology, Division of Cancer and Stem Cells, School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK

    Alaa T. Alshareeda

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  1. Alaa T. Alshareeda
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  2. Ola H. Negm
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  3. Andrew R. Green
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  7. Rebeka Sultana
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  9. Ian O. Ellis
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  10. Emad A. Rakha
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Corresponding author

Correspondence to Alaa T. Alshareeda.

Additional information

Ola H. Negm is first joint author for this study.

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Alshareeda, A.T., Negm, O.H., Green, A.R. et al. SUMOylation proteins in breast cancer. Breast Cancer Res Treat 144, 519–530 (2014). https://doi.org/10.1007/s10549-014-2897-7

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  • DOI: https://doi.org/10.1007/s10549-014-2897-7

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