Identification of Developmental Endothelial Locus-1 on Circulating Extracellular Vesicles as a Novel Biomarker for Early Breast Cancer Detection

Clin Cancer Res. 2016 Apr 1;22(7):1757-66. doi: 10.1158/1078-0432.CCR-15-0654. Epub 2015 Nov 24.


Purpose: Currently, there are no molecular biomarkers for the early detection of breast cancer. This study focused on identifying surface proteins found on circulating extracellular vesicles (EVs) for detecting early-stage breast cancer.

Experimental design: Circulating EVs, isolated from the plasma of 10 patients with breast cancer (stages I and II) and 5 healthy controls, were analyzed using LC-MS/MS. Developmental endothelial locus-1 protein (Del-1) was selected as a candidate biomarker. Two different ELISAs were used to measure Del-1 in plasma samples from healthy controls (n= 81), patients with breast cancer (n= 269), breast cancer patients after surgical resection (n= 50), patients with benign breast tumors (n= 64), and patients with noncancerous diseases (n= 98) in two cohorts.

Results: Plasma Del-1 levels were significantly higher (P< 0.0001) in patients with breast cancer than in all controls and returned to almost normal after tumor removal. The diagnostic accuracy of Del-1 was AUC, 0.961 [95% confidence interval (CI), 0.924-0.983], sensitivity of 94.70%, and specificity of 86.36% in test cohort and 0.968 (0.933-0.988), 92.31%, and 86.62% in validation cohort for early-stage breast cancer by one type of ELISA. Furthermore, Del-1 maintained diagnostic accuracy for patients with early-stage breast cancer using the other type of ELISA [0.946 (0.905-0.972), 90.90%, and 77.14% in the test cohort; 0.943 (0.900-0.971), 89.23%, and 80.99% in the validation cohort].

Conclusions: Del-1 on circulating EVs is a promising marker to improve identification of patients with early-stage breast cancer and distinguish breast cancer from benign breast tumors and noncancerous diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biomarkers, Tumor*
  • Breast Neoplasms / diagnosis*
  • Breast Neoplasms / metabolism*
  • Calcium-Binding Proteins
  • Carrier Proteins / metabolism*
  • Case-Control Studies
  • Cell Adhesion Molecules
  • Early Detection of Cancer*
  • Enzyme-Linked Immunosorbent Assay
  • Extracellular Vesicles / metabolism*
  • Female
  • Humans
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Staging
  • Proteomics / methods
  • ROC Curve
  • Reproducibility of Results
  • Sensitivity and Specificity


  • Biomarkers, Tumor
  • Calcium-Binding Proteins
  • Carrier Proteins
  • Cell Adhesion Molecules
  • EDIL3 protein, human