Skip to main content

Advertisement

SpringerLink
Log in

Prognostic effects of abnormal DNA damage response protein expression in breast cancer

  • Clinical trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

We aimed to explore the expression of DNA damage response machinery proteins and their integrated prognostic value in different subgroups of breast cancer.

Methods

Expression of NBS1, BRCA1, BRCA2, ATM, and p53 was determined by immunohistochemistry in 419 surgically resected breast tumors.

Results

Loss of NBS1, BRCA1, ATM, and abnormal p53 expression was significantly associated with lower disease-free survival rates. Abnormal DNA damage response protein expression, defined as loss of any one of NBS1, BRCA1, ATM, and/or abnormal p53 expression, was observed in 258 of 399 evaluable cases (64.7%) and was significantly associated with higher tumor grade, larger tumor size, and ER-negative, and/or PR-negative status. Most patients with luminal B (86.1%), HER2-enriched (94.4%), and triple-negative (86.8%) breast cancers had abnormal DNA damage response protein expression. In contrast, abnormal DNA damage response protein expression was found in only 53.8% of luminal A tumors. Abnormal DNA damage response protein expression was associated with significantly lower 5-year disease-free survival rates in all patients (95.6% vs. 84.8%, p = 0.001), as well as in the luminal A subgroup (97.4% vs. 89.0%, p = 0.011). In multivariate analysis, abnormal DNA damage response protein expression remained an independent predictor of shorter disease-free survival for luminal A subtype (hazard ratio 3.14, 95% confidence interval 1.16–8.47; p = 0.024).

Conclusion

Abnormal DNA damage response protein expression is found in most luminal B and HER2-enriched breast cancers as frequently as in triple-negative breast cancer. In the luminal A subtype, abnormal DNA damage response protein expression is an independent prognostic marker.

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

Similar content being viewed by others

References

  1. Stracker TH, Roig I, Knobel PA, Marjanović M (2013) The ATM signaling network in development and disease. Front Genet 4:37. https://doi.org/10.3389/fgene.2013.00037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Paull TT (2015) Mechanisms of ATM activation. Annu Rev Biochem 84:711–738. https://doi.org/10.1146/annurev-biochem-060614-034335

    Article  CAS  PubMed  Google Scholar 

  3. Lee J-M, Ledermann JA, Kohn EC (2014) PARP inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies. Ann Oncol 25:32–40. https://doi.org/10.1093/annonc/mdt384

    Article  PubMed  Google Scholar 

  4. Farmer H, McCabe N, Lord CJ et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–921. https://doi.org/10.1038/nature03445

    Article  CAS  PubMed  Google Scholar 

  5. Liu X, Holstege H, van der Gulden H et al (2007) Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer. Proc Natl Acad Sci USA 104:12111–12116. https://doi.org/10.1073/pnas.0702969104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Rizvi NA, Hellmann MD, Snyder A et al (2015) Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:124–128. https://doi.org/10.1126/science.aaa1348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Telli ML, Jensen KC, Vinayak S et al (2015) Phase II Study of gemcitabine, carboplatin, and iniparib as neoadjuvant therapy for triple-negative and BRCA1/2 mutation-associated breast cancer with assessment of a tumor-based measure of genomic instability: PrECOG 0105. J Clin Oncol 33:1895–1901. https://doi.org/10.1200/JCO.2014.57.0085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mulligan JM, Hill LA, Deharo S et al (2014) Identification and validation of an anthracycline/cyclophosphamide-based chemotherapy response assay in breast cancer. JNCI J Natl Cancer Inst. https://doi.org/10.1093/jnci/djt335

    Article  PubMed  Google Scholar 

  9. Suh KJ, Ryu HS, Lee K-H et al (2016) Loss of ataxia-telangiectasia-mutated protein expression correlates with poor prognosis but benefits from anthracycline-containing adjuvant chemotherapy in breast cancer. Breast Cancer Res Treat 158:233–241. https://doi.org/10.1007/s10549-016-3869-x

    Article  CAS  PubMed  Google Scholar 

  10. Hammond MEH, Hayes DF, Dowsett M et al (2010) American Society of Clinical Oncology/College of American Pathologists Guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 28:2784–2795. https://doi.org/10.1200/JCO.2009.25.6529

    Article  PubMed  PubMed Central  Google Scholar 

  11. Wolff AC, Hammond MEH, Hicks DG et al (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31:3997–4013. https://doi.org/10.1200/JCO.2013.50.9984

    Article  PubMed  Google Scholar 

  12. Goldhirsch A, Wood WC, Coates AS et al (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 22:1736–1747. https://doi.org/10.1093/annonc/mdr304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kim HS, Kim MA, Hodgson D et al (2013) Concordance of ATM (ataxia telangiectasia mutated) immunohistochemistry between biopsy or metastatic tumor samples and primary tumors in gastric cancer patients. Pathobiol J Immunopathol Mol Cell Biol 80:127–137. https://doi.org/10.1159/000346034

    Article  CAS  Google Scholar 

  14. Yemelyanova A, Vang R, Kshirsagar M et al (2011) Immunohistochemical staining patterns of p53 can serve as a surrogate marker for TP53 mutations in ovarian carcinoma: an immunohistochemical and nucleotide sequencing analysis. Mod Pathol 24:1248–1253. https://doi.org/10.1038/modpathol.2011.85

    Article  CAS  PubMed  Google Scholar 

  15. Boyle DP, McArt DG, Irwin G et al (2014) The prognostic significance of the aberrant extremes of p53 immunophenotypes in breast cancer. Histopathology 65:340–352. https://doi.org/10.1111/his.12398

    Article  PubMed  Google Scholar 

  16. Kim H, Saka B, Knight S et al (2014) Having pancreatic cancer with tumoral loss of ATM and normal TP53 protein expression is associated with a poorer prognosis. Clin Cancer Res 20:1865–1872. https://doi.org/10.1158/1078-0432.CCR-13-1239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. James CR, Quinn JE, Mullan PB et al (2007) BRCA1, a potential predictive biomarker in the treatment of breast cancer. Oncologist 12:142–150. https://doi.org/10.1634/theoncologist.12-2-142

    Article  CAS  PubMed  Google Scholar 

  18. Yang Q, Sakurai T, Mori I et al (2001) Prognostic significance of BRCA1 expression in Japanese sporadic breast carcinomas. Cancer 92:54–60

    Article  CAS  PubMed  Google Scholar 

  19. Abdel-Fatah TMA, Arora A, Alsubhi N et al (2014) Clinicopathological significance of ATM-Chk2 expression in sporadic breast cancers: a comprehensive analysis in large cohorts. Neoplasia 16:982–991. https://doi.org/10.1016/j.neo.2014.09.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bueno RC, Canevari RA, Villacis RR et al (2014) ATM down-regulation is associated with poor prognosis in sporadic breast carcinomas. Ann Oncol 25:69–75. https://doi.org/10.1093/annonc/mdt421

    Article  CAS  PubMed  Google Scholar 

  21. Bartkova J, Tommiska J, Oplustilova L et al (2008) Aberrations of the MRE11-RAD50-NBS1 DNA damage sensor complex in human breast cancer: MRE11 as a candidate familial cancer-predisposing gene. Mol Oncol 2:296–316. https://doi.org/10.1016/j.molonc.2008.09.007

    Article  PubMed  PubMed Central  Google Scholar 

  22. Aleskandarany M, Caracappa D, Nolan CC et al (2015) DNA damage response markers are differentially expressed in BRCA-mutated breast cancers. Breast Cancer Res Treat 150:81–90. https://doi.org/10.1007/s10549-015-3306-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sorlie T, Tibshirani R, Parker J et al (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100:8418–8423. https://doi.org/10.1073/pnas.0932692100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Parkes EE, Walker SM, McCabe N et al (2016) Abstract 4000: A DNA damage response deficiency (DDRD) group in breast cancer is associated with activation of the STING innate immune pathway and PD-L1 expression. Cancer Res 76:4000–4000. https://doi.org/10.1158/1538-7445.AM2016-4000

    Article  Google Scholar 

  25. Kim H-J, Min A, Im S-A et al (2017) Anti-tumor activity of the ATR inhibitor AZD6738 in HER2 positive breast cancer cells. Int J Cancer 140:109–119. https://doi.org/10.1002/ijc.30373

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT, and Future Planning (2015R1A2A2A01004655; to S.-A. Im). This work was also funded by a Grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI14C1277; to S.-A. Im), and was supported in part by Grant No. 04-2014-0570 from the Seoul National University Hospital Research Fund.

Author information

Authors and Affiliations

  1. Translational Medicine, Seoul National University College of Medicine, Seoul, Korea

    Koung Jin Suh, Yaewon Yang, Do-Youn Oh & Seock-Ah Im

  2. Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea

    Koung Jin Suh

  3. Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

    Han Suk Ryu, Hyojin Kim & In Ae Park

  4. Cancer Research Institute, Seoul National University, Seoul, Korea

    Han Suk Ryu, Kyung-Hun Lee, Ahrum Min, Tae-Yong Kim, Han-Byoel Lee, Hyeong-Gon Moon, Sae-Won Han, Do-Youn Oh, Wonshik Han, In Ae Park, Dong-Young Noh & Seock-Ah Im

  5. Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

    Kyung-Hun Lee, Tae-Yong Kim, Sae-Won Han, Do-Youn Oh & Seock-Ah Im

  6. Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea

    Han-Byoel Lee, Hyeong-Gon Moon, Wonshik Han & Dong-Young Noh

  7. Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju, Republic of Korea

    Yaewon Yang

Authors
  1. Koung Jin Suh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Han Suk Ryu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kyung-Hun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hyojin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ahrum Min
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tae-Yong Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yaewon Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Han-Byoel Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hyeong-Gon Moon
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sae-Won Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Do-Youn Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Wonshik Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. In Ae Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Dong-Young Noh
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Seock-Ah Im
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Kyung-Hun Lee or Seock-Ah Im.

Ethics declarations

Conflict of interest

Authors have no conflict of interest to declare.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 52 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Suh, K.J., Ryu, H.S., Lee, KH. et al. Prognostic effects of abnormal DNA damage response protein expression in breast cancer. Breast Cancer Res Treat 175, 117–127 (2019). https://doi.org/10.1007/s10549-019-05128-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-019-05128-9

Keywords

Search

Navigation