The online version of this article (doi:10.1186/bcr3176) contains supplementary material, which is available to authorized users.
Max Yan, Huiling Xu contributed equally to this work.
The authors declare that they have no competing interests.
MY contributed to the conception and design of the study, analyzed the data, and drafted and revised the manuscript. HX contributed to the conception and design of the study, performed the immunohistochemistry, and revised the manuscript. NW performed the CGH and mRNA array experiments. KS performed the miRNA experiments. IH contributed to the statistical analysis and design of the miRNA array experiments. kConFab contributed to the provision of study materials and the collection of clinicopathologic and follow-up survival data. MJM contributed to the conception and design of the study and the analysis, drafting, and revision of the manuscript. SBF contributed to the conception and design of the study, provision of study materials, analysis, drafting, and revision of the manuscript. All authors read and approved the final manuscript.
The RAD21 gene encodes a key component of the cohesin complex, which is essential for chromosome segregation, and together with BRCA1 and BRCA2, for high-fidelity DNA repair by homologous recombination. Although its expression correlates with early relapse and treatment resistance in sporadic breast cancers, it is unclear whether familial breast cancers behave in a similar manner.
We performed an immunohistochemical analysis of RAD21 expression in a cohort of 94 familial breast cancers (28 BRCA1, 27 BRCA2, and 39 BRCAX) and correlated these data with genotype and clinicopathologic parameters, including survival. In these cancers, we also correlated RAD21 expression with genomic expression profiling and gene copy-number changes and miRNAs predicted to target RAD21.
No significant differences in nuclear RAD21 expression were observed between BRCA1 (12 (43%) of 28), BRCA2 (12 (44%) of 27), and BRCAX cancers (12 (33%) of 39 (p = 0.598). No correlation was found between RAD21 expression and grade, size, or lymph node, ER, or HER2 status (all P > 0.05). As for sporadic breast cancers, RAD21 expression correlated with shorter survival in grade 3 (P = 0.009) and but not in grade 1 (P = 0.065) or 2 cancers (P = 0.090). Expression of RAD21 correlated with poorer survival in patients treated with chemotherapy (P = 0.036) but not with hormonal therapy (P = 0.881). RAD21 expression correlated with shorter survival in BRCA2 (P = 0.006) and BRCAX (P = 0.008), but not BRCA1 cancers (P = 0.713). Changes in RAD21 mRNA were reflected by genomic changes in DNA copy number (P < 0.001) and by RAD21 protein expression, as assessed with immunohistochemistry (P = 0.047). High RAD21 expression was associated with genomic instability, as assessed by the total number of base pairs affected by genomic change (P = 0.048). Of 15 miRNAs predicted to target RAD21, mir-299-5p inversely correlated with RAD21 expression (P = 0.002).
Potential use of RAD21 as a predictive and prognostic marker in familial breast cancers is hence feasible and may therefore take into account the patient's BRCA1/2 mutation status.
Additional file 1: Table S1. Flow of familial breast cancer patients through the study, according to REMARK criteria. (DOC 30 KB)13058_2011_2980_MOESM1_ESM.DOC
Additional file 2: Table S2. Nuclear RAD21 expression in familial breast cancers (score out of 7). (DOC 36 KB)13058_2011_2980_MOESM2_ESM.DOC
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- Enhanced RAD21 cohesin expression confers poor prognosis in BRCA2 and BRCAX, but not BRCA1 familial breast cancers
Michael J McKay
Stephen B Fox
- BioMed Central
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