Enhanced RAD21 cohesin expression confers poor prognosis and resistance to chemotherapy in high grade luminal, basal and HER2 breast cancers
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McKay, Michael; Xu, Huiling; Yan, Max; Patra, Jennifer; Natrajan, Rachael; Yan, Yuqian; Swagemakers, Sigrid; Tomaszewski, Jonathan; Verschoor, Sandra; Millar, Ewan KA; van der Spek, Peter
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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...[Show more]
dc.contributor.author | McKay, Michael | |
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dc.contributor.author | Xu, Huiling | |
dc.contributor.author | Yan, Max | |
dc.contributor.author | Patra, Jennifer | |
dc.contributor.author | Natrajan, Rachael | |
dc.contributor.author | Yan, Yuqian | |
dc.contributor.author | Swagemakers, Sigrid | |
dc.contributor.author | Tomaszewski, Jonathan | |
dc.contributor.author | Verschoor, Sandra | |
dc.contributor.author | Millar, Ewan KA | |
dc.contributor.author | van der Spek, Peter | |
dc.date.accessioned | 2015-12-10T22:27:29Z | |
dc.identifier.issn | 1465-542X | |
dc.identifier.uri | http://hdl.handle.net/1885/54228 | |
dc.description.abstract | 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. | |
dc.publisher | Current Science Inc | |
dc.source | Breast Cancer Research (Online edition) | |
dc.subject | Keywords: antineoplastic agent; cohesin; cyclophosphamide; doxorubicin; epidermal growth factor receptor 2; estrogen receptor; etoposide; fluorouracil; messenger RNA; methotrexate; protein rad21; unclassified drug; adult; aged; article; breast cancer; cancer adjuva | |
dc.title | Enhanced RAD21 cohesin expression confers poor prognosis and resistance to chemotherapy in high grade luminal, basal and HER2 breast cancers | |
dc.type | Journal article | |
local.description.notes | Imported from ARIES | |
local.identifier.citationvolume | 13 | |
dc.date.issued | 2011 | |
local.identifier.absfor | 111204 - Cancer Therapy (excl. Chemotherapy and Radiation Therapy) | |
local.identifier.ariespublication | f5625xPUB295 | |
local.type.status | Published Version | |
local.contributor.affiliation | McKay, Michael, College of Medicine, Biology and Environment, ANU | |
local.contributor.affiliation | Xu, Huiling, Peter MacCallum Cancer Centre | |
local.contributor.affiliation | Yan, Max, Peter MacCallum Cancer Centre | |
local.contributor.affiliation | Patra, Jennifer, Peter MacCallum Cancer Centre | |
local.contributor.affiliation | Natrajan, Rachael, Institute of Cancer Research, London | |
local.contributor.affiliation | Yan, Yuqian, Peter MacCallum Cancer Centre | |
local.contributor.affiliation | Swagemakers, Sigrid, Erasmus University | |
local.contributor.affiliation | Tomaszewski, Jonathan, Peter MacCallum Cancer Centre | |
local.contributor.affiliation | Verschoor, Sandra, Peter MacCallum Cancer Centre | |
local.contributor.affiliation | Millar, Ewan KA, Garvan Institute of Medical Research | |
local.contributor.affiliation | van der Spek, Peter, Erasmus University | |
local.description.embargo | 2037-12-31 | |
local.bibliographicCitation.issue | 1 | |
local.bibliographicCitation.startpage | 1 | |
local.bibliographicCitation.lastpage | 10 | |
local.identifier.doi | 10.1186/bcr2814 | |
dc.date.updated | 2016-02-24T09:04:14Z | |
local.identifier.scopusID | 2-s2.0-84860389200 | |
Collections | ANU Research Publications |
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