The Expression Level of HJURP has an Independent Prognostic Impact and Predicts the Sensitivity to Radiotherapy in Breast Cancer

Zhi Hu; Ge Huang; Anguraj Sadanandam; Shenda Gu; Marc E Lenburg; Melody Pai; Nora Bayani; Eleanor A Blakely; Joe W Gray; Jian-Hua Mao

Disclosures

Breast Cancer Res 

In This Article

Abstract and Introduction

Abstract

Introduction HJURP (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.
Methods We 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.
Results HJURP 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.
Conclusions HJURP 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.

Introduction

The centromere has long been recognized as a locus important for proper cell division and accurate partitioning of chromosomes into daughter cells.[1–3] Centromeres are the chromatin regions associated with kinetochores, which are massive multi-protein complexes that mediate chromosome segregation and the mitotic checkpoint.[4] There is mounting evidence that kinetochores become functionally unstable during oncogenesis resulting in segregation defects, chromosome instability, and cancer development.[4–6]

Holliday Junction Recognition Protein (HJURP, also known as hFLEG1), which is a newly discovered gene, was reported to be overexpressed in lung cancer cells through genome-wide expression profile analysis.[7] By quantitative RT-PCR, Valente et al found that the HJURP expression levels significantly differ between glioblastoma resection tumor and non-neoplastic white matter.[8] Additionally it was observed that the expression level of HJURP in glioblastoma was changed about nine fold compared to typically benign pilocytic astrocytomas by microarray profile analysis.[9] It has also been reported that HJURP is involved in DNA double-strand break repair pathway through interaction with MSH5 and NBS1.[7] Recently two groups have shown that HJURP functions at the level of the centromere, and is required for centromere protein A (CENPA) centromeric localization, for loading of new CENPA nucleosomes, and for accurate chromosomal segregation.[10–12] A majority of cancer cells tend to gain and lose chromosomes at each mitotic division and are found to be aneuploid and chromosomally instable. Thus these findings support the hypothesis that alterations in HJURP might play an important role in cancer development. We investigated whether altered expression levels of HJURP are associated with adverse clinical outcomes using cohorts of patients with breast cancer.

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