Enhanced RAD21 cohesin expression confers poor prognosis and resistance to chemotherapy in high grade luminal, basal and HER2 breast cancers

Breast Cancer Res. 2011 Jan 21;13(1):R9. doi: 10.1186/bcr2814.


Introduction: RAD21 is a component of the cohesin complex, which is essential for chromosome segregation and error-free DNA repair. We assessed its prognostic and predictive power in a cohort of in situ and invasive breast cancers, and its effect on chemosensitivity in vitro.

Methods: RAD21 immunohistochemistry was performed on 345 invasive and 60 pure in situ carcinomas. Integrated genomic and transcriptomic analyses were performed on a further 48 grade 3 invasive cancers. Chemosensitivity was assessed in breast cancer cell lines with an engineered spectrum of RAD21 expression.

Results: RAD21 expression correlated with early relapse in all patients (hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.06 to 2.86, P = 0.029). This was due to the effect of grade 3 tumors (but not grade 1 or 2) in which RAD21 expression correlated with early relapse in luminal (P = 0.040), basal (P = 0.018) and HER2 (P = 0.039) groups. In patients treated with chemotherapy, RAD21 expression was associated with shorter overall survival (P = 0.020). RAD21 mRNA expression correlated with DNA copy number, with amplification present in 32% (7/22) of luminal, 31% (4/13) of basal and 22% (2/9) of HER2 grade 3 cancers. Variations in RAD21 mRNA expression in the clinical samples were reflected in the gene expression data from 36 breast cancer cell lines. Knockdown of RAD21 in the MDA-MB-231 breast cancer cell line significantly enhanced sensitivity to cyclophosphamide, 5-fluorouracil and etoposide. The findings for the former two drugs recapitulated the clinical findings.

Conclusions: RAD21 expression confers poor prognosis and resistance to chemotherapy in high grade luminal, basal and HER2 breast cancers. RAD21 may be a novel therapeutic target.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology*
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cluster Analysis
  • DNA Copy Number Variations
  • DNA-Binding Proteins
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Gene Amplification
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Humans
  • Kaplan-Meier Estimate
  • Neoplasm Grading
  • Neoplasm Staging
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • RNA, Small Interfering
  • Receptor, ErbB-2 / metabolism*


  • Antineoplastic Agents
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Phosphoproteins
  • RAD21 protein, human
  • RNA, Small Interfering
  • Receptor, ErbB-2