Enhanced RAD21 cohesin expression confers poor prognosis in BRCA2 and BRCAX, but not BRCA1 familial breast cancersReport as inadecuate




Enhanced RAD21 cohesin expression confers poor prognosis in BRCA2 and BRCAX, but not BRCA1 familial breast cancers - Download this document for free, or read online. Document in PDF available to download.

Breast Cancer Research

, 14:R69

First Online: 26 April 2012Received: 09 December 2011Revised: 26 February 2012Accepted: 26 April 2012

Abstract

IntroductionThe 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.

MethodsWe 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.

ResultsNo 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.

ConclusionsPotential 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.

AbbreviationsBRCA1breast cancer 1, early onset

BRCA2breast cancer 2, early onset

CGHchromogenic hybridization

CISHchromogenic in situ hybridization

CNVcopy-number variation

DCISductal carcinoma in situ

DSBdouble-stranded break

ERestrogen receptor

HER2human epidermal growth receptor 2

HRhomologous recombination

miRNAmicroRNA

PARPpoly-ADP ribose polymerase

SNPsingle-nucleotide polymorphism.

Electronic supplementary materialThe 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.

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Author: Max Yan - Huiling Xu - Nic Waddell - Kristy Shield-Artin - Izhak Haviv - kConFab authors - Michael J McKay - Stephen B Fo

Source: https://link.springer.com/article/10.1186/bcr3176



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