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: