Skip to main content

Advertisement

SpringerLink
Log in

Higher cytoplasmic and nuclear poly(ADP-ribose) polymerase expression in familial than in sporadic breast cancer

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Poly(ADP-ribose) polymerase 1 (PARP) is a key element of the single-base excision pathway for repair of DNA single-strand breaks. To compare the cytoplasmic and nuclear poly(ADP-ribose) expression between familial (BRCA1, BRCA2, or non BRCA1/2) and sporadic breast cancer, we investigated 39 sporadic and 39 familial breast cancer cases. The two groups were matched for hormone receptor status and human epidermal growth factor receptor 2 status. Additionally, they were matched by grading with a maximum difference of ±1 degree (e.g., G2 instead of G3). Cytoplasmic PARP (cPARP) expression was significantly higher in familial compared to sporadic breast cancer (P = 0.008, chi-squared test for trends) and a high nuclear PARP expression (nPARP) was significantly more frequently observed in familial breast cancer (64 %) compared with sporadic breast cancer (36 %) (P = 0.005, chi-squared test). The overall PARP expression was significantly higher in familial breast cancer (P = 0.042, chi-squared test). In familial breast cancer, a combination of high cPARP and high nPARP expression is the most common (33 %), whereas in sporadic breast cancer, a combination of low cPARP and intermediate nPARP expression is the most common (39 %). Our results show that the overall PARP expression in familial breast cancer is higher than in sporadic breast cancer which might suggest they might respond better to treatment with PARP inhibitors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

HR:

Hormone receptor

IDC:

Invasive ductal carcinoma

ILC:

Invasive lobular carcinoma

References

  1. Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin 62(1):10–29

    Article  PubMed  Google Scholar 

  2. Lee E-H, Park SK, Park B, Kim S-W, Lee MH, Ahn SH, Son BH, Yoo K-Y, Kang D (2010) Effect of BRCA1/2 mutation on short-term and long-term breast cancer survival: a systematic review and meta-analysis. Breast Cancer Res Treat 122(1):11–25

    Article  PubMed  CAS  Google Scholar 

  3. Murphy CG, Moynahan ME (2010) BRCA gene structure and function in tumor suppression: a repair-centric perspective. Cancer J 16(1):39–47

    Article  PubMed  CAS  Google Scholar 

  4. Bane A, O’Malley FP (2006) Familial breast cancer. In: Kuhn B (ed) Breast pathology. Churchill Livingstone Elsevier, Philadelphia, pp 241–248

    Google Scholar 

  5. Osin PP, Lakhani SR (1999) The pathology of familial breast cancer immunohistochemistry and molecular analysis. Breast Cancer Res 1(1):36–40

    Article  PubMed  CAS  Google Scholar 

  6. Turner N, Tutt A, Ashworth A (2004) Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer 4(10):814–819

    Article  PubMed  CAS  Google Scholar 

  7. van der Groep P, van der Wall E, van Diest P (2011) Pathology of hereditary breast cancer. Cell Oncol (Dordr) 34(2):71–88

    Google Scholar 

  8. Anders C, Carey LA (2008) Understanding and treating triple-negative breast cancer. Oncology (Williston Park) 22(11):1233–1243

    Google Scholar 

  9. Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thürlimann B, Senn HJ, Panel M (2011) Strategies for subtypes dealing with the diversity of breast cancer: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2011. Ann Oncol 22(8):1736–1747

    Article  PubMed  CAS  Google Scholar 

  10. Byrski T, Gronwald J, Huzarski T, Grzybowska E, Budryk M, Stawicka M, Mierzwa T, Szwiec M, Wisniowski R, Siolek M, Dent R, Lubinski J, Narod S (2010) Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol 28(3):375–379

    Article  PubMed  CAS  Google Scholar 

  11. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O’Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JHM, de Bono JS (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361(2):123–134

    Article  PubMed  CAS  Google Scholar 

  12. Leung M, Rosen D, Fields S, Cesano A, Budman DR (2011) Poly(ADP-ribose) polymerase-1 inhibition: preclinical and clinical development of synthetic lethality. Mol Med 17(7–8):854–862

    PubMed  CAS  Google Scholar 

  13. Schreiber V, Amé J, Dollé P, Schultz I, Rinaldi B, Fraulob V, Ménissier-de Murcia J, de Murcia G (2002) Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1. J Biol Chem 277(25):23028–23036

    Article  PubMed  CAS  Google Scholar 

  14. Calvert H, Azzariti A (2011) The clinical development of inhibitors of poly(ADP-ribose) polymerase. Ann Oncol 22(suppl 1):i53–i59

    Article  PubMed  Google Scholar 

  15. Annunziata CM, O’Shaughnessy J (2010) Poly (ADP-ribose) polymerase as a novel therapeutic target in cancer. Clin Cancer Res 16(18):4517–4526

    Article  PubMed  CAS  Google Scholar 

  16. Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, Friedlander M, Arun B, Loman N, Schmutzler RK, Wardley A, Mitchell G, Earl H, Wickens M, Carmichael J (2010) Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376(9737):235–244

    Article  PubMed  CAS  Google Scholar 

  17. Patel AG, De Lorenzo SB, Flatten KS, Poirier GG, Kaufmann SH (2012) Failure of iniparib to inhibit poly(ADP-ribose) polymerase in vitro. Clin Cancer Res 18(6):1655–1662

    Article  PubMed  CAS  Google Scholar 

  18. Development Core Team R (2011) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna

    Google Scholar 

  19. von Minckwitz G, Müller BM, Loibl S, Budczies J, Hanusch C, Darb-Esfahani S, Hilfrich J, Weiss E, Huober J, Blohmer JU, du Bois A, Zahm D-M, Khandan F, Hoffmann G, Gerber B, Eidtmann H, Fend F, Dietel M, Mehta K, Denkert C (2011) Cytoplasmic poly(adenosine diphosphate ribose) polymerase expression is predictive and prognostic in patients with breast cancer treated with neoadjuvant chemotherapy. J Clin Oncol 29(16):2150–2157

    Article  Google Scholar 

  20. Domagala P, Huzarski T, Lubinski J, Gugala K, Domagala W (2011) PARP-1 expression in breast cancer including BRCA1-associated triple negative and basal-like tumors: possible implications for PARP-1 inhibitor therapy. Breast Cancer Res Treat 127(3):861–869

    Article  PubMed  CAS  Google Scholar 

  21. Ozretić L, Rhiem K, Huss S, Wappenschmidt B, Markiefka B, Sinn P, Schmutzler RK, Buettner R (2011) High nuclear poly(adenosine diphosphate-ribose) polymerase expression is predictive for BRCA1- and BRCA2-deficient breast cancer. J Clin Oncol 29(34):4586–4588

    Article  PubMed  Google Scholar 

  22. Ossovskaya V, Chou Koo I, Kaldjian EP, Alvares C, Sherman BM (2010) Upregulation of poly (ADP-ribose) polymerase-1 (PARP1) in triple-negative breast cancer and other primary human tumor types. Genes Cancer 1(8):812–821

    Article  PubMed  CAS  Google Scholar 

  23. Krishnakumar R, Kraus WL (2010) The PARP side of the nucleus: molecular actions, physiological outcomes, and clinical targets. Mol Cell 39(1):8–24

    Article  PubMed  CAS  Google Scholar 

  24. Wang J, Bian C, Li J, Couch FJ, Wu K, Zhao RC (2008) Poly(ADP-ribose) polymerase-1 down-regulates BRCA2 expression through the BRCA2 promoter. J Biol Chem 283(52):36249–36256

    Article  PubMed  CAS  Google Scholar 

  25. Hegan DCLY, Stachelek GC, Crosby ME, Bindra RS, Glazer PM (2010) Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130. Proc Natl Acad Sci U S A 107(5):2201–2206

    Article  PubMed  CAS  Google Scholar 

  26. Patel AGSJ, Kaufmann SH (2011) Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. Proc Natl Acad Sci U S A 108(8):3406–3411

    Article  PubMed  CAS  Google Scholar 

  27. Kurian AW, Gong GD, John EM, Johnston DA, Felberg A, West DW, Miron A, Andrulis IL, Hopper JL, Knight JA, Ozcelik H, Dite GS, Apicella C, Southey MC, Whittemore AS (2011) Breast cancer risk for noncarriers of family-specific BRCA1 and BRCA2 mutations: findings from the breast cancer family registry. J Clin Oncol 29(34):4505–4509

    Article  PubMed  CAS  Google Scholar 

  28. Elston C, Ellis I (1991) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19(5):403–410

    Article  PubMed  CAS  Google Scholar 

  29. Subramanian A, Salhab M, Mokbel K (2008) Oestrogen producing enzymes and mammary carcinogenesis: a review. Breast Cancer Res Treat 111(2):191–202

    Article  PubMed  CAS  Google Scholar 

  30. Arun B, Bayraktar S, Liu DD, Gutierrez Barrera AM, Atchley D, Pusztai L, Litton JK, Valero V, Meric-Bernstam F, Hortobagyi GN, Albarracin C (2011) Response to neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers: a single-institution experience. J Clin Oncol 29(28):3739–3746

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank Petra Wachs and Ines Koch for their excellent technical assistance as well as Martina Eickmann, Catarina Liebscher, and Britta Dahl for proofreading.

Conflict of interests

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Institute of Pathology, Charité University Hospital, Campus Mitte, Charitéplatz 1, 10117, Berlin, Germany

    Jan Budczies, Judith Prinzler, Manfred Dietel, Carsten Denkert & Berit Maria Müller

  2. Radboud University Nijmegen Medical Centre, Geert Grooteplein-Zuid 10, 6525 GA, Nijmegen, the Netherlands

    Marie-Luise Klauke

  3. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Geert Grooteplein-Zuid 10, 6525 GA, Nijmegen, the Netherlands

    Nicoline Hoogerbrugge

  4. Department of Pathology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, the Netherlands

    Peter Bult & J. Han J. M. van Krieken

  5. Institute of Pathology, DRK Kliniken Berlin Westend, Spandauer Damm 130, 14050, Berlin, Germany

    Cornelia Radke

Authors
  1. Marie-Luise Klauke
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicoline Hoogerbrugge
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jan Budczies
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter Bult
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Judith Prinzler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cornelia Radke
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J. Han J. M. van Krieken
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Manfred Dietel
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Carsten Denkert
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Berit Maria Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Berit Maria Müller.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Klauke, ML., Hoogerbrugge, N., Budczies, J. et al. Higher cytoplasmic and nuclear poly(ADP-ribose) polymerase expression in familial than in sporadic breast cancer. Virchows Arch 461, 425–431 (2012). https://doi.org/10.1007/s00428-012-1311-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-012-1311-2

Keywords

Search

Navigation