The expression level of HJURP has an independent prognostic impact and predicts the sensitivity to radiotherapy in breast cancer

Abstract

IntroductionHJURP (Holliday Junction Recognition Protein) is a newly discovered gene reported to function at centromeres and to interact with CENPA. However its role in tumor development remains largely unknown. The goal of this study was to investigate the clinical significance of HJURP in breast cancer and its correlation with radiotherapeutic outcome.MethodsWe measured HJURP expression level in human breast cancer cell lines and primary breast cancers by Western blot and/or by Affymetrix Microarray; and determined its associations with clinical variables using standard statistical methods. Validation was performed with the use of published microarray data. We assessed cell growth and apoptosis of breast cancer cells after radiation using high-content image analysis.ResultsHJURP was expressed at higher level in breast cancer than in normal breast tissue. HJURP mRNA levels were significantly associated with estrogen receptor (ER), progesterone receptor (PR), Scarff-Bloom-Richardson (SBR) grade, age and Ki67 proliferation indices, but not with pathologic stage, ERBB2, tumor size, or lymph node status. Higher HJURP mRNA levels significantly decreased disease-free and overall survival. HJURP mRNA levels predicted the prognosis better than Ki67 proliferation indices. In a multivariate Cox proportional-hazard regression, including clinical variables as covariates, HJURP mRNA levels remained an independent prognostic factor for disease-free and overall survival. In addition HJURP mRNA levels were an independent prognostic factor over molecular subtypes (normal like, luminal, Erbb2 and basal). Poor clinical outcomes among patients with high HJURP expression were validated in five additional breast cancer cohorts. Furthermore, the patients with high HJURP levels were much more sensitive to radiotherapy. In vitro studies in breast cancer cell lines showed that cells with high HJURP levels were more sensitive to radiation treatment and had a higher rate of apoptosis than those with low levels. Knock down of HJURP in human breast cancer cells using shRNA reduced the sensitivity to radiation treatment. HJURP mRNA levels were significantly correlated with CENPA mRNA levels.ConclusionsHJURP mRNA level is a prognostic factor for disease-free and overall survival in patients with breast cancer and is a predictive biomarker for sensitivity to radiotherapy.

Molecular features of triple negative breast cancer cells by genome-wide gene expression profiling analysis

“…CENPF is also reportedly upregulated in head and neck squamous cell carcinomas and pancreatic ductal carcinomas (46,47). NDC80 and HJURP are reportedly overexpressed in breast cancers and associated with tumor grade and poor prognosis (48,49). These findings suggest that aberrant regulation of kinetochore assembly and centromere function through mitosis might contribute to the carcinogenesis of TNBC and that destroying one component of the kinetochore, such as targeting CENPK, might be a novel molecular target for TNBC treatment.…”

C2ORF40suppresses breast cancer cell proliferation and invasion through modulating expression of M phase cell cycle genes

“…Retroviral particles were produced as described previously. 27,28 Briefly, C2ORF40 (or control empty) retroviral vectors along with packaging system methylation of these CpG sites was found in primary cancer tissues and commonly used cell lines. 16 Furthermore, this hypermethylation strongly correlates with expression of C2ORF40 in breast cancers.…”

Breast cancer subtypes: response to radiotherapy and potential radiosensitisation

“…In breast cancers, expression levels of Holliday junction recognition protein (HJURP) mRNA can predict patient survival after RT [17] and high cytoplasmic expression of peroxiredoxin-I correlated with increased LRs after RT [18]. However, in most cases, predictive and prognostic information from potential biomarkers has not been separated.…”

“…Several potential predictive biomarkers that may correlate with RT response have been identified [17][18][19]. In breast cancers, expression levels of Holliday junction recognition protein (HJURP) mRNA can predict patient survival after RT [17] and high cytoplasmic expression of peroxiredoxin-I correlated with increased LRs after RT [18].…”