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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.

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