Tumor Biology

, Volume 37, Issue 10, pp 13855–13870 | Cite as

Identification of novel biomarkers associated with poor patient outcomes in invasive breast carcinoma

  • Renata A. Canevari
  • Fabio A. Marchi
  • Maria A. C. Domingues
  • Victor Piana de Andrade
  • José R. F. Caldeira
  • Sergio Verjovski-Almeida
  • Silvia R. Rogatto
  • Eduardo M. Reis
Original Article


Breast carcinoma (BC) corresponds to 23 % of all cancers in women, with 1.38 million new cases and 460,000 deaths worldwide annually. Despite the significant advances in the identification of molecular markers and different modalities of treatment for primary BC, the ability to predict its metastatic behavior is still limited. The purpose of this study was to identify novel molecular markers associated with distinct clinical outcomes in a Brazilian cohort of BC patients. We generated global gene expression profiles using tumor samples from 24 patients with invasive ductal BC who were followed for at least 5 years, including a group of 15 patients with favorable outcomes and another with nine patients who developed metastasis. We identified a set of 58 differentially expressed genes (p ≤ 0.01) between the two groups. The prognostic value of this metastasis signature was corroborated by its ability to stratify independent BC patient datasets according to disease-free survival and overall survival. The upregulation of B3GNT7, PPM1D, TNKS2, PHB, and GTSE1 in patients with poor outcomes was confirmed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) in an independent sample of patients with BC (47 with good outcomes and eight that presented metastasis). The expression of BCL2-associated agonist of cell death (BAD) protein was determined in 1276 BC tissue samples by immunohistochemistry and was consistent with the reduced BAD mRNA expression levels in metastatic cases, as observed in the oligoarray data. These findings point to novel prognostic markers that can distinguish breast carcinomas with metastatic potential from those with favorable outcomes.


Breast cancer Prognostic gene signature Metastasis Gene expression Tumor biomarkers 



This work was mainly supported by a grant from the Conselho Nacional de Desenvolvimento Científico e Tecnologico (CNPq) (Edital MCT/CNPq/CT-Biotecnologia n° 010/2004). Additional funding was provided by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP). E.M.R. and S.V.A. received investigator fellowship awards from CNPq. The authors thank Sandra Dringo Linde for her expert technical assistance during this study.

Authors’ contributions

SVA, SRR, and EMR conceived and designed the experiments. RAC and MACD performed the experiments. EMR, FM, and RAC analyzed data. JRFC and VPA contributed samples. RAC, FM, VPA, SRR, and EMR drafted or revised the manuscript. All authors read and approved the final manuscript.

Compliance with ethical standards

Written informed consent was obtained from all patients during the collection period, and the study was reviewed and approved by the Ethics Committees from both institutions (CEP FHAC 340/04 and CEP ACCC 1155/08).

Conflicts of interest


Supplementary material

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Supplementary Figure 1 (PDF 445 kb)
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Supplementary Table 1 (PDF 144 kb)
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Supplementary Table 2 (PDF 149 kb)
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Supplementary Table 3 (PDF 144 kb)
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Supplementary Table 4 (PDF 142 kb)
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Supplementary Table 7 (PDF 139 kb)


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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Renata A. Canevari
    • 1
  • Fabio A. Marchi
    • 2
  • Maria A. C. Domingues
    • 3
  • Victor Piana de Andrade
    • 4
  • José R. F. Caldeira
    • 5
  • Sergio Verjovski-Almeida
    • 6
    • 7
  • Silvia R. Rogatto
    • 2
    • 8
    • 9
  • Eduardo M. Reis
    • 6
  1. 1.Instituto de Pesquisa e DesenvolvimentoUniversidade do Vale do ParaíbaSão José dos CamposBrazil
  2. 2.CIPE - AC Camargo Cancer CenterSão PauloBrazil
  3. 3.Departamento de Patologia, Faculdade de MedicinaUniversidade do Estado de São Paulo - UNESPBotucatuBrazil
  4. 4.Departamento de PatologiaAC Camargo Cancer CenterSão PauloBrazil
  5. 5.Departamento de SenologiaHospital Amaral CarvalhoJaúBrazil
  6. 6.Departamento de Bioquímica, Instituto de QuímicaUniversidade de São Paulo - USPSão PauloBrazil
  7. 7.Instituto ButantanSão PauloBrazil
  8. 8.Department of Clinical Genetics Vejle SygehusVejleDenmark
  9. 9.Institute of Regional Health, University of Southern DenmarkVejleDenmark

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