AGR3 in breast cancer: prognostic impact and suitable serum-based biomarker for early cancer detection

PLoS One. 2015 Apr 15;10(4):e0122106. doi: 10.1371/journal.pone.0122106. eCollection 2015.

Abstract

Blood-based early detection of breast cancer has recently gained novel momentum, as liquid biopsy diagnostics is a fast emerging field. In this study, we aimed to identify secreted proteins which are up-regulated both in tumour tissue and serum samples of breast cancer patients compared to normal tissue and sera. Based on two independent tissue cohorts (n = 75 and n = 229) and one serum cohort (n = 80) of human breast cancer and healthy serum samples, we characterised AGR3 as a novel potential biomarker both for breast cancer prognosis and early breast cancer detection from blood. AGR3 expression in breast tumours is significantly associated with oestrogen receptor α (P<0.001) and lower tumour grade (P<0.01). Interestingly, AGR3 protein expression correlates with unfavourable outcome in low (G1) and intermediate (G2) grade breast tumours (multivariate hazard ratio: 2.186, 95% CI: 1.008-4.740, P<0.05) indicating an independent prognostic impact. In sera analysed by ELISA technique, AGR3 protein concentration was significantly (P<0.001) elevated in samples from breast cancer patients (n = 40, mainly low stage tumours) compared to healthy controls (n = 40). To develop a suitable biomarker panel for early breast cancer detection, we measured AGR2 protein in human serum samples in parallel. The combined AGR3/AGR2 biomarker panel achieved a sensitivity of 64.5% and a specificity of 89.5% as shown by receiver operating characteristic (ROC) curve statistics. Thus our data clearly show the potential usability of AGR3 and AGR2 as biomarkers for blood-based early detection of human breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / blood
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Blotting, Western
  • Breast Neoplasms / diagnosis*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Carrier Proteins / blood
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cohort Studies
  • Early Diagnosis*
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunohistochemistry / statistics & numerical data
  • Kaplan-Meier Estimate
  • Middle Aged
  • Mucoproteins
  • Multivariate Analysis
  • Neoplasm Proteins / blood
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Oncogene Proteins
  • Prognosis
  • Proportional Hazards Models
  • Proteins / metabolism
  • ROC Curve
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • AGR2 protein, human
  • AGR3 protein, human
  • Biomarkers, Tumor
  • Carrier Proteins
  • Mucoproteins
  • Neoplasm Proteins
  • Oncogene Proteins
  • Proteins

Grants and funding

Funding provided by INTERREG IV-A MicroBioMed EMR. INT4-1.2.-2009-11/058 (ED), http://www.interregemr.eu/, http://www.microbiomed.ulg.ac.be/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.