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BRCA1 promoter methylation is a marker of better response to anthracycline-based therapy in sporadic TNBC

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Abstract

The aim of the current study was to investigate the role of BRCA1 gene aberrations in sporadic triple-negative breast cancer (TNBC) and its impact on anthracycline-based therapy. BRCA1 promoter methylation was analyzed in 70 TNBC and compared with the clinical and pathologic characteristics. As a control group, we used 70 patients with non-TNBC. BRCA1 promoter methylation was observed in 65.2 % of patients and was similar in both groups. BRCA1 promoter methylation was associated with decreased intensity of BRCA1 protein expression (P = 0.002) and significant increase of median disease-free survival (DFS) of TNBC patients receiving adjuvant anthracycline-based chemotherapy (P = 0.001). Multivariate analysis revealed that BRCA1 promoter methylation remains a favorable factor in regard to DFS (HR 0.224; 95 % CI 0.092–0.546, P = 0.001) in TNBC after adjustment for other prognostic factors. In contrast, in non-TNBC, BRCA1 promoter methylation was not associated with any clinical and pathologic parameters. BRCA1 promoter methylation is a common mechanism of BRCA1 gene aberration in sporadic breast cancer and is predictive for better response to anthracycline-based therapies.

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References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249

    Article  PubMed  Google Scholar 

  2. Perou CM, Sorlie T, Eisen MB, van de RM, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406:747–752

    Article  PubMed  CAS  Google Scholar 

  3. Reddy KB (2011) Triple-negative breast cancers: an updated review on treatment options. Curr Oncol 18:e173–e179

    Article  PubMed  CAS  Google Scholar 

  4. Caestecker KW, Van de Walle GR (2012) The role of BRCA1 in DNA double-strand repair: past and present. Exp Cell Res 319:575–587

    Google Scholar 

  5. Catteau A, Morris JR (2002) BRCA1 methylation: a significant role in tumour development? Semin Cancer Biol 12:359–371

    Article  PubMed  CAS  Google Scholar 

  6. Kennedy RD, Quinn JE, Mullan PB, Johnston PG, Harkin DP (2004) The role of BRCA1 in the cellular response to chemotherapy. J Natl Cancer Inst 96:1659–1668

    Article  PubMed  CAS  Google Scholar 

  7. Dhillon KK, Swisher EM, Taniguchi T (2011) Secondary mutations of BRCA1/2 and drug resistance. Cancer Sci 102:663–669

    Article  PubMed  CAS  Google Scholar 

  8. Ignatov A, Bischoff J, Ignatov T, Schwarzenau C, Krebs T, Kuester D, Costa SD, Roessner A, Semczuk A, Schneider-Stock R (2010) APC promoter hypermethylation is an early event in endometrial tumorigenesis. Cancer Sci 101:321–327

    Article  PubMed  CAS  Google Scholar 

  9. Ignatov A, Ignatov T, Weissenborn C, Eggemann H, Bischoff J, Semczuk A, Roessner A, Costa SD, Kalinski T (2011) G-protein-coupled estrogen receptor GPR30 and tamoxifen resistance in breast cancer. Breast Cancer Res Treat 128:457–466

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  11. Knudson AG Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820–823

    Article  Google Scholar 

  12. Sherr CJ (2004) Principles of tumor suppression. Cell 116:235–246

    Article  PubMed  CAS  Google Scholar 

  13. Suijkerbuijk KP, Fackler MJ, Sukumar S, van Gils CH, van Laar T, van der WE, Vooijs M, van Diest PJ (2008) Methylation is less abundant in BRCA1-associated compared with sporadic breast cancer. Ann Oncol 19:1870–1874

    Article  PubMed  CAS  Google Scholar 

  14. Galizia E, Giorgetti G, Piccinini G, Santinelli A, Loretelli C, Bianchi F, Gagliardini D, Carbonari G, Pisa E, Belvederesi L, Bracci R, Ferretti C, Corradini F, Cellerino R (2010) BRCA1 expression in triple negative sporadic breast cancers. Anal Quant Cytol Histol 32:24–29

    PubMed  Google Scholar 

  15. Holm K, Hegardt C, Staaf J, Vallon-Christersson J, Jonsson G, Olsson H, Borg A, Ringner M (2010) Molecular subtypes of breast cancer are associated with characteristic DNA methylation patterns. Breast Cancer Res 12:R36

    Article  PubMed  Google Scholar 

  16. Rice JC, Ozcelik H, Maxeiner P, Andrulis I, Futscher BW (2000) Methylation of the BRCA1 promoter is associated with decreased BRCA1 mRNA levels in clinical breast cancer specimens. Carcinogenesis 21:1761–1765

    Article  PubMed  CAS  Google Scholar 

  17. Rennstam K, Ringberg A, Cunliffe HE, Olsson H, Landberg G, Hedenfalk I (2010) Genomic alterations in histopathologically normal breast tissue from BRCA1 mutation carriers may be caused by BRCA1 haploinsufficiency. Genes Chromosomes Cancer 49:78–90

    Article  PubMed  CAS  Google Scholar 

  18. Guendel I, Carpio L, Pedati C, Schwartz A, Teal C, Kashanchi F, Kehn-Hall K (2010) Methylation of the tumor suppressor protein, BRCA1, influences its transcriptional cofactor function. PLoS One 5:e11379

    Article  PubMed  Google Scholar 

  19. Gluz O, Liedtke C, Gottschalk N, Pusztai L, Nitz U, Harbeck N (2009) Triple-negative breast cancer–current status and future directions. Ann Oncol 20:1913–1927

    Article  PubMed  CAS  Google Scholar 

  20. Fedier A, Steiner RA, Schwarz VA, Lenherr L, Haller U, Fink D (2003) The effect of loss of Brca1 on the sensitivity to anticancer agents in p53-deficient cells. Int J Oncol 22:1169–1173

    PubMed  CAS  Google Scholar 

  21. Sylvain V, Lafarge S, Bignon YJ (2002) Dominant-negative activity of a Brca1 truncation mutant: effects on proliferation, tumorigenicity in vivo, and chemosensitivity in a mouse ovarian cancer cell line. Int J Oncol 20:845–853

    PubMed  CAS  Google Scholar 

  22. Tassone P, Tagliaferri P, Perricelli A, Blotta S, Quaresima B, Martelli ML, Goel A, Barbieri V, Costanzo F, Boland CR, Venuta S (2003) BRCA1 expression modulates chemosensitivity of BRCA1-defective HCC1937 human breast cancer cells. Br J Cancer 88:1285–1291

    Article  PubMed  CAS  Google Scholar 

  23. Chappuis PO, Goffin J, Wong N, Perret C, Ghadirian P, Tonin PN, Foulkes WD (2002) A significant response to neoadjuvant chemotherapy in BRCA1/2 related breast cancer. J Med Genet 39:608–610

    Article  PubMed  CAS  Google Scholar 

  24. Goffin JR, Chappuis PO, Begin LR, Wong N, Brunet JS, Hamel N, Paradis AJ, Boyd J, Foulkes WD (2003) Impact of germline BRCA1 mutations and overexpression of p53 on prognosis and response to treatment following breast carcinoma: 10-year follow up data. Cancer 97:527–536

    Article  PubMed  CAS  Google Scholar 

  25. Margeli M, Cirauqui B, Castella E, Tapia G, Costa C, Gimenez-Capitan A, Barnadas A, Sanchez RM, Benlloch S, Taron M, Rosell R (2010) The prognostic value of BRCA1 mRNA expression levels following neoadjuvant chemotherapy in breast cancer. PLoS One 5:e9499

    Article  PubMed  Google Scholar 

  26. Wang L, Wei J, Qian X, Yin H, Zhao Y, Yu L, Wang T, Liu B (2008) ERCC1 and BRCA1 mRNA expression levels in metastatic malignant effusions is associated with chemosensitivity to cisplatin and/or docetaxel. BMC Cancer 8:97

    Article  PubMed  Google Scholar 

  27. Egawa C, Motomura K, Miyoshi Y, Takamura Y, Taguchi T, Tamaki Y, Inaji H, Koyama H, Noguchi S (2003) Increased expression of BRCA1 mRNA predicts favorable response to anthracycline-containing chemotherapy in breast cancers. Breast Cancer Res Treat 78:45–50

    Article  PubMed  CAS  Google Scholar 

  28. Kirova YM, Stoppa-Lyonnet D, Savignoni A, Sigal-Zafrani B, Fabre N, Fourquet A (2005) Risk of breast cancer recurrence and contralateral breast cancer in relation to BRCA1 and BRCA2 mutation status following breast-conserving surgery and radiotherapy. Eur J Cancer 41:2304–2311

    Article  PubMed  Google Scholar 

  29. Silver DP, Richardson AL, Eklund AC, Wang ZC, Szallasi Z, Li Q, Juul N, Leong CO, Calogrias D, Buraimoh A, Fatima A, Gelman RS, Ryan PD, Tung NM, De Nicolo A, Ganesan S, Miron A, Colin C, Sgroi DC, Ellisen LW, Winer EP, Garber JE (2010) Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. J Clin Oncol 28:1145–1153

    Article  PubMed  CAS  Google Scholar 

  30. Xu Y, Diao L, Chen Y, Liu Y, Wang C, Ouyang T, Li J, Wang T, Fan Z, Fan T, Lin B, Deng D, Narod SA, Xie Y (2013) Promoter methylation of BRCA1 in triple-negative breast cancer predicts sensitivity to adjuvant chemotherapy. Ann Oncol 24:1498–1505

    Article  PubMed  CAS  Google Scholar 

  31. Dejeux E, Ronneberg JA, Solvang H, Bukholm I, Geisler S, Aas T, Gut IG, Borresen-Dale AL, Lonning PE, Kristensen VN, Tost J (2010) DNA methylation profiling in doxorubicin treated primary locally advanced breast tumours identifies novel genes associated with survival and treatment response. Mol Cancer 9:68

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank Carola Kügler, Claudia Miethke, and Nadine Wiest, from the molecular genetics lab, and the whole team of the laboratory of immunohistochemistry for their excellent technical assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Otto-von-Guericke University, G.-Hauptmann Str. 35, 39108, Magdeburg, Germany

    T. Ignatov, A. Ignatov, S. D. Costa & J. Bischoff

  2. Department of Pathology, Otto-von-Guericke University, Magdeburg, Germany

    A. Poehlmann, A. Schinlauer, A. Roessner & T. Kalinski

  3. Department of Obstetrics and Gynecology, University Medical Center Regensburg, Regensburg, Germany

    A. Ignatov

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  1. T. Ignatov
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  2. A. Poehlmann
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  4. A. Schinlauer
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  5. S. D. Costa
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Correspondence to A. Ignatov.

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Ignatov, T., Poehlmann, A., Ignatov, A. et al. BRCA1 promoter methylation is a marker of better response to anthracycline-based therapy in sporadic TNBC. Breast Cancer Res Treat 141, 205–212 (2013). https://doi.org/10.1007/s10549-013-2693-9

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  • DOI: https://doi.org/10.1007/s10549-013-2693-9

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