The current study is the first to report that HJURP is overexpressed in breast cancer cell lines and primary human breast cancer compared to non-malignant human mammary epithelial cells and normal breast tissues. High HJURP mRNA expression is significantly associated with both shorter disease-free and overall survival which were validated in five independent clinical datasets for breast cancer. Furthermore, HJURP is a predictive marker for sensitivity of radiotherapy, indicating levels of HJURP mRNA and protein in breast cancer patients are clinically relevant.
Although we found HJURP
mRNA levels were not associated with ERBB2 status, the mRNA levels of HJURP
was still found significantly higher in triple-negative (ER negative, PR negative, ERBB2/HER2/neu not overexpressed) breast cancer, possibly due to the fact that a higher HJURP
mRNA level is significantly associated with ER or PR negative status. Triple negative breast cancer has distinct clinical and pathological features, and also has relatively poor prognosis and aggressive behavior [18
], consistent with our finding that high HJURP
expression is associated with a bad prognosis. Furthermore, our studies showed that the prognostic effect of HJURP
mRNA level on survival is independent of the clinical factors, such as age, lymph node, pathological stage, SBR grade, ER, PR, tumor size, and the molecular subtypes. In addition, we found there is a significant correlation between HJURP
expression and Ki67 proliferation indices; however, HJURP
expression is a better biomarker than Ki67 proliferation indices for the predication of prognosis.
It is very interesting to find that the HJURP
mRNA level is a predictive marker for radiotherapy sensitivity. Our results showed that patients with low mRNA levels of HJURP
already had a good prognosis and could not get further benefit from radiotherapy, suggesting these patients may not necessarily benefit from receiving radiotherapy. However, patients with high HJURP
mRNA levels could increase their survival with radiotherapy, but they still had a worse prognosis than those with low levels as found in Dataset 3 (Figure ) and Dataset 4 (Figure ) where almost all patients received radiotherapy with or without additional benefit. Thus a high level of HJURP
is overall associated with poor prognosis. Although we note our findings will require replication in additional independent and larger cohorts, our in vitro
studies further confirmed that breast cancer cells with high levels of HJURP
are more sensitive to radiation treatment, and even more convincingly, knock down of HJURP
by shRNA reduces the sensitivity to radiation. The radiation induced more apoptosis in these cells, consistent with clinical findings. A previous report showed that HJURP
interacts with proteins hMSH5 and NBS1, suggesting HJURP
is involved in the DNA double-strand break repair process [7
]. The understanding of the roles that HJURP
plays in DNA repair and cell death in response to DNA damage may provide new insights into the molecular mechanisms of breast tumor development and may help to improve breast cancer therapies. In addition, we found that cells with HJURP
shRNA grew slowly (data not shown), which is consistent with the finding that the double time of cell lines was negatively correlated with HJURP
protein level, indicating HJURP
plays an important role in cell proliferation. Thus one of the reasons why the ability of HJURP
to act as a marker for prognosis and response to radiotherapy may be linked to its control of cell proliferation.
has recently been reported to interact with CENP-A for the purpose of localizing CENP-A and loading new CENP-A nucleosomes on the centromere [11
]. CENP-A is the key determinant of centromere formation and kinetochore assembly, which regulate the complex job of attaching chromosomes to the mitotic spindle; ensuring that those attachments are correct; signalling a delay in mitotic progression if they are not, and regulating the movements of the chromosomes towards the spindle poles in anaphase. Thus overexpression of HJURP
in human breast cancer may be similar to overexpression of mitotic kinases, such as Aurora kinases, which induce genomic instability that is one of the hallmarks for tumor development. In this study we showed that HJURP
mRNA levels are highly significantly correlated with CENPA mRNA levels in human breast cancer cell lines and primary breast tumors. Such correlation is also found in other types of human cancer, such as cancers from lung, ovary, prostate (data not shown), suggesting that compatible mRNA levels of HJURP
and CENPA might be required for tumor progression. Further investigation of the interaction between HJURP
and CENPA for breast cancer development will be carried out in our future studies.