Breast Cancer Research and Treatment

, Volume 178, Issue 1, pp 185–197 | Cite as

Risk stratification of triple-negative breast cancer with core gene signatures associated with chemoresponse and prognosis

  • Eun-Kyu Kim
  • Ae Kyung Park
  • Eunyoung Ko
  • Woong-Yang Park
  • Kyung-Min Lee
  • Dong-Young Noh
  • Wonshik HanEmail author



Neoadjuvant chemotherapy studies have consistently reported a strong correlation between pathologic response and long-term outcome in triple-negative breast cancer (TNBC). We aimed to define minimal gene signatures for predicting chemoresponse by a three-step approach and to further develop a risk-stratification method of TNBC.


The first step involved the detection of genes associated with resistance to docetaxel in eight TNBC cell lines, leading to identification of thousands of candidate genes. Through subsequent second and third step analyses with gene set enrichment analysis and survival analysis using public expression profiles, the candidate gene list was reduced to prognostic core gene signatures comprising ten or four genes.


The prognostic core gene signatures include three up-regulated (CEBPD, MMP20, and WLS) and seven down-regulated genes (ASF1A, ASPSCR1, CHAF1B, DNMT1, GINS2, GOLGA2P5, and SKA1). We further develop a simple risk-stratification method based on expression profiles of the core genes. Relative expression values of the up-regulated and down-regulated core genes were averaged into two scores, Up and Down scores, respectively; then samples were stratified by a diagonal line in a xy plot of the Up and Down scores. Based on this method, the patients were successfully divided into subgroups with distinct chemoresponse and prognosis. The prognostic power of the method was validated in three independent public datasets containing 230, 141, and 117 TNBC patients with chemotherapy. In multivariable Cox regression analysis, the core gene signatures were significantly associated with prognosis independent of tumor stage and age at diagnosis. In meta-analysis, we found that five core genes (CEBPD, WLS, CHAF1B, GINS2, and SKA1) play opposing roles, either tumor promoter or suppressor, in TNBC and non-TNBC tumors respectively, depending on estrogen receptor status.


The results may provide a promising prognostic tool for predicting chemotherapy responders among TNBC patients prior to initiation of chemotherapeutic treatment.


Triple-negative breast cancer Chemoresponse Core gene Risk stratification Prognosis 



We thank all the individuals who took part in the Translational Research Organization in Cancer (TROICA) project and all the researchers who have enabled this work to be carried out.


This research was funded by grants of the National Research Foundation (NRF) of Korea funded by the Korea government (MSIP), 2015R1A2A2A01008264 (to WH) and 2015R1A4A1041219 (to AKP).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Not applicable.

Supplementary material

10549_2019_5366_MOESM1_ESM.pdf (19.9 mb)
Supplementary material 1 (PDF 20340 kb)
10549_2019_5366_MOESM2_ESM.xlsx (26 kb)
Supplementary material 2 (XLSX 26 kb)


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Authors and Affiliations

  1. 1.Department of SurgerySeoul National University Bundang Hospital, Seoul National University College of MedicineSeongnamRepublic of Korea
  2. 2.College of Pharmacy and Research Institute of Life and Pharmaceutical SciencesSunchon National UniversitySuncheonRepublic of Korea
  3. 3.Department of Surgical Oncology, Oncology CenterSheikh Khalifa Specialty HospitalRas Al-KhaimahUnited Arab Emirates
  4. 4.Department of Molecular Cell Biology, Samsung Medical Center and Samsung Genome InstituteSungkyunkwan University School of MedicineSeoulRepublic of Korea
  5. 5.Cancer Research InstituteSeoul National University College of MedicineSeoulRepublic of Korea
  6. 6.Department of SurgerySeoul National University Hospital, Seoul National University College of MedicineSeoulRepublic of Korea

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