At last, a predictive and prognostic marker for radiotherapy?
Breast Cancer Research volume 12, Article number: 106 (2010)
Holliday junction recognition protein (HJURP) levels in breast cancer associate with both poor prognosis and an increased sensitivity to irradiation. Whilst, in part, this could be explained in relation to proliferation, it would not entirely account for the association with sensitivity to radiation. Thus, HJURP may have clinical potential as a marker of prognosis and radiation sensitivity; further validation with tissues from randomised controlled trials is needed. HJURP may represent the first in a class of proteins with roles in chromosome segregation and DNA repair that act as predictive biomarkers.
Hu and colleagues  have risen to the challenge of seeking to identify a prognostic and predictive marker of sensitivity to radiotherapy in breast cancer. Radiotherapy for patients with breast cancer improves local disease control, and relapse free and overall survival . Like most therapies, this comes at the cost of some morbidity [2, 3], which is the driver for technical refinements in radiotherapy, including hypofractionation, partial breast radiation and intraoperative radiotherapy, with increasing use and development of radiotherapy predicted for the future . There are significant benefits in targeting systemic breast cancer treatment, using, for example, oestrogen receptor (ER), or HER2 receptor expression. Transcriptome profiling may be used not only to categorise breast cancers, but in practice and randomised controlled trials to guide therapy . In contrast, few inroads have been made into identifying prognostic or predictive biomarkers for radiotherapy in breast (or indeed any other) cancer .
Hu and colleagues  have made a bold attempt to address both biomarker questions in a single study. In 130 patient samples and 4 breast cell lines, they examined Holliday junction recognition protein (HJURP), required for centromere protein A (CENPA) localisation [7–9] and involved in repairing double-strand DNA breaks . By protein (western blot) and mRNA level (which at least in cell lines correlated), HJURP expression was higher in cancers than normal tissues and was associated with poor prognostic features, including ER-negative, high grade and high Ki67 proliferation index cancers. Remarkably, HJURP, divided empirically into high, mid and low tertiles, was an independent prognostic variable for disease free and overall survival in 130 women with breast cancer and outperformed many conventional prognostic features. The prognostic hypothesis was tested and replicated on transcriptome data from five further publicly available data sets, confirming the association between high HJURP mRNA and prognosis. However, an independent association with radiotherapy outcomes as opposed to overall systemic outcomes (disease-free survival and overall survival) requires elucidation. Furthermore, questions regarding differing radio therapy regimens, breast conservation or mastectomy, extent of radiotherapy and differences in systemic therapy may all have a bearing on outcomes but were clearly beyond the remit of this study .
The allied mechanistic questions examined in vitro showed two breast cancer cell lines with high HJURP were more sensitive to radiation (via apoptosis) than two immortal lines with low levels of HJURP; HJURP levels were associated with CENPA, and HJURP knockdown reduced sensitivity to radiation. Subgroup analyses noted patients with high tumour HJURP given radiotherapy had a better disease-free survival than those who did not receive radiotherapy, suggesting the cell line studies were clinically relevant. Is HJURP the driving force for radiation sensitivity, or does it reflect another aspect of tumour pathobiology? If radiation sensitivity is related to the role of HJURP in DNA damage repair, cells with higher HJURP should show enhanced repair and, therefore, radiation resistance, contrary to the data obtained. On the other hand, both HJURP and CENPA are cell cycle regulated to achieve their functions in chromosome segregation [8, 9] and proliferating cells are generally radiosensitive compared to non-proliferating cells. HJURP may simply reflect proliferation, evidenced by the reduced proliferation in the HJURP knockdown cells, which become radioresistant. However, that HJURP is associated with radiation response suggests levels of HJURP are ineffective for repair, and the cells lack other repair pathways. Increased HJURP may therefore result from failed attempts to repair ongoing damage. Alternatively, increased HJURP may indicate a block in cell cycle at a stage that is susceptible to radiotherapy, leading to hyper-activation of HJURP (and CENPA). Indeed, proliferation itself (measured by Ki67) is not a strong pretreatment indicator of response, whereas mitosis shows a significant association with chemo/radiotherapy outcome . Thus, HJURP may act as a predictive marker because of its dual roles in accurate chromosome segregation during mitosis and in DNA repair and may represent the first example of this class of predictive biomarkers.
Regardless of the mechanism(s) involved, the prognostic potential will require testing in large randomised clinical trials of radiotherapy [3, 12]. However, in most clinical and trials settings, formalin fixed paraffin embedded tissues may be the sole tissue resource available and while mRNA analyses are possible on such material, immunohistochemistry delineating the cell distribution of HJURP protein (cancer cell or stroma, tumour periphery, heterogeneous or homogeneous distribution) may be helpful. In trials, patient variables are balanced and should provide the potential to address the issue of sensitivity to radiation. A role for HJURP in normal (breast) tissues may also predict which patients might show increased sensitivity to radiotherapy and so indicate patients who would get excessive early or late radiotherapy effects .
While the data presented here  are inevitably preliminary, the ability to predict tumour sensitivity to radiotherapy in a way analogous to ER or HER2 is an intriguing prospect.
In HJURP, do we at last have a predictive and prognostic marker for who should (or should not) have radiotherapy? It is too soon to be sure, but HJURP clearly merits evaluation and requires validation as a prognostic and predictive marker in the multimodality treatment of breast cancer.
centromere protein A
holliday junction recognition protein.
Hu Z, Huang G, Sadanandam A, Gu S, Lenburg ME, Pai M, Bayani N, Blakely EA, Gray JW, Mao J-H: The expression level of HJURP has an independent prognostic impact and predicts the sensitivity to radiotherapy in breast cancer. Breast Cancer Res. 2010, 12: R18-10.1186/bcr2487.
Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans E, Godwin J, Gray R, Hicks C, James S, MacKinnon E, McGale P, McHugh T, Peto R, Taylor C, Wang Y, Early Breast Cancer Trialists' Collaborative Group (EBCTCG): Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005, 366: 2087-2106.
START Trialists' Group, Bentzen SM, Agrawal RK, Aird EG, Barrett JM, Barrett-Lee PJ, Bliss JM, Brown J, Dewar JA, Dobbs HJ, Haviland JS, Hoskin PJ, Hopwood P, Lawton PA, Magee BJ, Mills J, Morgan DA, Owen JR, Simmons S, Sumo G, Sydenham MA, Venables K, Yarnold JR: The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet Oncol. 2008, 9: 331-341. 10.1016/S1470-2045(08)70077-9.
Hiley C, Tutt A, Torres M, Palmieri C: Adjuvant radiotherapy for breast cancer. BMJ. 2008, 337: a2843-10.1136/bmj.b4.
Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, Somerfield MR, Hayes DF, Bast RC: American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer. J Clin Oncol. 2007, 25: 5287-5312. 10.1200/JCO.2007.14.2364.
Riesterer O, Milas L, Ang KK: Use of molecular biomarkers for predicting the response to radiotherapy with or without chemotherapy. J Clin Oncol. 2007, 25: 4075-4083. 10.1200/JCO.2007.11.8497.
Sanchez-Pulido L, Pidoux AL, Ponting CP, Allshire RC: Common ancestry of the CENP-A chaperones Scm3 and HJURP. Cell. 2009, 137: 1173-1174. 10.1016/j.cell.2009.06.010.
Dunleavy EM, Roche D, Tagami H, Lacoste N, Ray-Gallet D, Nakamura Y, Daigo Y, Nakatani Y, Almouzni-Pettinotti G: HJURP is a cell-cycle-dependent maintenance and deposition factor of CENP-A at centromeres. Cell. 2009, 137: 485-497. 10.1016/j.cell.2009.02.040.
Foltz DR, Jansen LE, Bailey AO, Yates JR, Bassett EA, Wood S, Black BE, Cleveland DW: Centromere-specific assembly of CENP-a nucleosomes is mediated by HJURP. Cell. 2009, 137: 472-484. 10.1016/j.cell.2009.02.039.
Kato T, Sato N, Hayama S, Yamabuki T, Ito T, Miyamoto M, Kondo S, Nakamura Y, Daigo Y: Activation of Holliday junction recognizing protein involved in the chromosomal stability and immortality of cancer cells. Cancer Res. 2007, 67: 8544-8553. 10.1158/0008-5472.CAN-07-1307.
Chakravarthy AB, Kelley MC, McLaren B, Truica CI, Billheimer D, Meyer IA, Grau AM, Johnson DH, Simpson JF, Beauchamp RD, Jones C, Pientenpol JA: Neoadjuvant concurrent paclitaxel and radiation in stage II/III breast cancer. Clin Cancer Res. 2006, 12: 1570-1576. 10.1158/1078-0432.CCR-05-2304.
START Trialists' Group, Bentzen SM, Agrawal RK, Aird EG, Barrett JM, Barrett-Lee PJ, Bentzen SM, Bliss JM, Brown J, Dewar JA, Dobbs HJ, Haviland JS, Hoskin PJ, Hopwood P, Lawton PA, Magee BJ, Mills J, Morgan DA, Owen JR, Simmons S, Sumo G, Sydenham MA, Venables K, Yarnold JR: The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet. 2008, 371: 1098-1107. 10.1016/S0140-6736(08)60348-7.
Liu Y, Appleyard MVCL, Coates PJ, Thompson AM: P53 and gamma irradiation in the normal breast. Int J Radiat Biol. 2009, 85: 1026-1031. 10.3109/09553000903261271.
The authors declare that they have no competing interests.
About this article
Cite this article
Coates, P., Dewar, J. & Thompson, A.M. At last, a predictive and prognostic marker for radiotherapy?. Breast Cancer Res 12, 106 (2010). https://doi.org/10.1186/bcr2567