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. 2012 Oct 15;14(6):860–863. doi: 10.1038/aja.2012.107

Overexpression of ETS-1 is associated with malignant biological features of prostate cancer

Bo Li 1,2, Yosuke Shimizu 1, Takashi Kobayashi 1,3, Naoki Terada 1, Koji Yoshimura 1, Tomomi Kamba 1, Yoshiki Mikami 4, Takahiro Inoue 1, Hiroyuki Nishiyama 5, Osamu Ogawa 1
PMCID: PMC3720114  PMID: 23064684

Abstract

E26 transformation-specific-1 (ETS-1), an ETS family transcription factor, has been reported to play an important role in a variety of physiological and pathological processes, but clinical implications of ETS-1 expression in prostate cancer (PCa), particularly high-risk cases, including response to androgen-deprivation therapy (ADT) have yet to be elucidated. We examined the expression of ETS-1 using immunohistochemical staining of paraffin-embedded prostate carcinoma tissue obtained by needle biopsy from 69 mostly advanced PCa patients. ETS-1 expression was compared with the clinicopathological characteristics of the 69 patients, including 25 who underwent ADT as a primary treatment. As a result, PCa patients with higher expression of ETS-1 were significantly more likely to be of high stage and high Gleason score (P<0.05). There was no significant association between ETS-1 expression and the initial prostate-specific antigen (PSA) level. In the 25 patients treated by ADT, the staining score for ETS-1 was significantly associated with rapid development of castration-resistant disease within 24 months (P<0.05), whereas the Gleason score and PSA level were not. In conclusion, increased ETS-1 expression was associated with a higher stage, higher Gleason score and shorter time to castration-resistant progression. These data suggest that immunostaining for ETS-1 could be a molecular marker for predicting a poor clinical outcome for PCa patients, particularly those with high-risk disease.

Keywords: castration resistant, E26 transformation-specific-1 (ETS-1), immunohistochemistry, prostate cancer

Introduction

Prostate cancer (PCa) is the most commonly diagnosed malignancy among males in the developed countries and the second leading cause of cancer-related mortality.1 Patients with low-risk localized disease can be cured with surgery or radiation, whereas patients with high-risk or advanced disease have a poor prognosis. Although hormonal therapy in the form of medical or surgical castration can induce disease remissions even in these advanced cases, development of castration-resistant prostate cancer (CRPC) is eventually inevitable. In terms of treatment outcome, duration of the disease remission is critical for patient survival since therapeutic options for CRPC are limited and prognosis is poor, with a median survival of less than 2 years.2,3 However, there has been limited knowledge of pre-treatment prognostic factors for clinical outcome of high-risk or advanced PCa patients.4,5,6 Thus, there is an urgent need to establish new prognostic markers to aid in the prediction of unfavorable prognostic groups.

E26 transformation-specific-1 (ETS-1) was originally characterized as the v-ets retroviral gene, one of the two oncogenes (v-myb and v-ets) in the avian leukemia retrovirus E26. ETS-1 has been reported to play an important role in a variety of physiological and pathological processes, including embryogenesis, wound healing and tumor progression, attributed to its ability to regulate the expression of proteins involved in angiogenesis, invasion and metastasis.7,8 It has been reported that ETS-1 is induced by some growth factor signals, including vascular endothelial growth factor and both acidic and basic fibroblast growth factors,9 and activates transcription of various metastasis-, angiogenesis- and invasion-associated genes, including genes encoding matrix metalloproteinases, urokinase-type plasminogen activator, and genes involved in energy metabolism.7,10

In fact, previous studies showed close associations between ETS-1 expression in the primary tumor and local or metastatic progression of the tumor in human colorectal,11 breast,12,13 lung,14 gastric15,16 and ovarian cancers,17 indicating that ETS-1 expression is a useful marker for predicting metastasis and disease outcome in patients with malignancies. In terms of prostate tumor, a recent report showed that ETS-1 could be a tumor marker for the differentiation of latent prostatic carcinoma from clinically significant disease.18 The authors observed significant increases in ETS-1 expression along with progression through benign, latent and clinical PCa patients. They also reported that higher ETS-1 expression was associated with higher histological grade in both latent and clinical PCa tissues. A more recent report also showed a significant correlation between ETS-1 expression and histological grade of PCa.19 They also showed that ETS-1 activation can promote castration-resistant progression of PCa cells. However, the clinical significance of ETS-1 expression among relatively advanced PCa patients has yet to be elucidated. In the present study, we investigated the significance of ETS-1 expression in the prediction of treatment outcome of advanced PCa patients.

Materials and methods

Patients' characteristics

Samples of prostatic needle biopsy were obtained from 69 Asian patients diagnosed with prostatic adenocarcinoma at Kyoto University Hospital, Kyoto, Japan. Clinical charts of the 69 patients were reviewed for their clinicopathological characteristics and most of the cases had a metastatic or high-risk disease as evident in Table 1. Mean (±s.e.) age and prostate-specific antigen (PSA) were 72.4±1.0 years and 428±197 ng ml−1, respectively. This study was approved by the Institutional Review Board of Kyoto University Graduate School of Medicine (G-52) and each patient provided a written informed consent for the use of their tissue samples.

Table 1. Clinicopathological characteristics of the 69 prostate cancer patients.

Variable n (%)
Age (year)  
 ≤70 27 (39.1)
 >70 42 (60.9)
Clinical stage  
 Localized 20 (29.0)
 Locally advanced 18 (26.1)
 Metastatic 31 (44.9)
Gleason score  
 6–7 40 (58.0)
 8–10 29 (42.0)
Initial PSA (ng ml−1)  
 <10 18 (26.1)
 10–20 14 (20.3)
 >20 37 (53.6)
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Abbreviation: PSA, prostate-specific antigen.

There were 31 patients with metastatic disease, and 25 of them (the mean age at the time of biopsy was 74.6±7.7 years) were available for follow-up data after androgen-deprivation therapy (ADT) based on goserelin acetate or leuprolide acetate. The 25 patients were additionally reviewed with regard to the time from the initiation of ADT to the development of CRPC, defined as three consecutive monthly increases in PSA against hormonal therapy including antiandrogens. The patients were followed until 31 May 2009, at the mean follow-up of 39.8 (s.e. 4.9) months. During this follow-up, 16 (64%) patients developed CRPC within 24 months, while nine (36%) were still responsive to ADT at the time of 24 months.

Immunohistochemical examination

Prostate biopsy specimens from the 69 patients were obtained before any kind of treatment. Paraffin-embedded sections were examined with immunohistochemical (IHC) staining. Material handling and immunostaining were performed according to methods described previously.18,20 Antigen retrieval was done with the microwave method. Briefly, citrate buffer (pH 6.0) was boiled for 10 min in a pressure-proof rice cooker (Rakuchin Gozen; Daiya, Tokyo, Japan) by microwave. Glass slides were put into a metal rack and boiled for another 20 min in the rice cooker. Endogenous peroxidase activity was blocked by 0.3% H2O2 in methyl alcohol for 30 min. ETS-1 (C-20) affinity-purified rabbit polyclonal antibody (Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA) was used at a dilution of 1∶500. We confirmed, using western blotting, that the antibody recognizes ETS-1 but not ERG, ETV1 or ETV4 (data not shown). After overnight incubation with primary antibody at 4°C, samples were then incubated with biotinylated antirabbit immunoglobulin G (Vector Laboratories, Burlingame, CA, USA) diluted to 1∶300 for 40 min. Avidin–biotin–peroxidase complex (ABC-Elite; Vector Laboratories, Burlingame, CA, USA) at a dilution of 1∶100 was applied for 50 min. The coloring reaction was carried out with 0.3 mg ml−1 of diaminobenzidine and 0.003% H2O2 and nuclei were counterstained with hematoxylin. For negative control, the primary antibody was omitted.

The histopathological examination for ETS-1 expression and Gleason score was performed by two of the authors (Y Shimizu and Y Mikami), who were blinded to the clinicopathological data. ETS-1 expression levels were graded as 0, 1 and 2 based on staining intensity to represent a range from no staining to strong staining.

Statistical analyses

Since immunohisochemical intensity was scored as categorical (0, 1 or 2) and therefore those values did not follow the Gaussian distribution, the Pearson Chi-square test or Fisher's exact probability test was used to analyze the association between the expression of ETS-1 and Gleason score, tumor stage, patients' age and PSA level as appropriate. All statistical analyses were performed using SPSS 16.0 software (IBM, Armonk, NY, USA) and P<0.05 was considered statistically significant.

Results

IHC for ETS-1 demonstrated signals both in the nucleus and cytoplasm of prostatic tumor cells but not in the adjacent benign tissues (Figure 1). There was a highly significant difference in the staining scores for ETS-1 among tumors at different clinical stage (P=0.04; Table 2). Interestingly, eight (89%) of the nine patients with a score of 2 had locally advanced or metastatic tumors. There was a statistically significant association among the staining scores for ETS-1 and the tumor's Gleason score (P=0.03). There was no significant association of the staining scores for ETS-1 with PSA levels (P=0.11) and age (P=0.91).

Figure 1.

Figure 1

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Immunohistochemistry of ETS-1 in prostatic carcinomas. It should be noted that heterogeneous expression of ETS-1 is observed both in the cytoplasm and the nucleus of the tumor cells. (a) No staining (staining score 0). (b) Weak staining (staining score 1). (c) Strong staining (staining score 2). (d) Negative control. Note that adjacent benign prostatic epithelia show negative stainings (e, f). Scale bars=50 µm. EST-1, E26 transformation-specific-1.

Table 2. Expression of ETS-1 in relation to clinicopathological characteristics.

Variable N Case No. in different group of ETS-1 expression score P
    0 (%) 1 (%) 2 (%)  
Clinical stage          
 Localized 20 13 (65) 6 (30) 1 (5) 0.04
 Locally advanced 18 8 (44) 6 (33) 4 (22)  
 Metastatic 31 8 (26) 19 (61) 4 (13)  
Gleason score          
 6 or less 8 7 (88) 1 (12) 0 (0) 0.03
 7 32 17 (53) 11 (34) 4 (13)  
 8–10 29 5 (17) 19 (66) 5 (17)  
Age (years)          
 ≤70 27 12 (44) 12 (44) 3 (11) 0.91
 >70 42 17 (40) 19 (45) 6 (14)  
Initial PSA (ng ml−1)          
 <10 18 8 (44) 8 (44) 2 (11) 0.11
 10–20 14 9 (64) 2 (14) 3 (21)  
 >20 37 12 (32) 21 (57) 4 (11)  
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Abbreviations: ETS-1, E26 transformation-specific-1; PSA, prostate-specific antigen.

For the 25 patients with metastatic PCa treated by ADT, there was a significant difference in the staining scores for ETS-1 between patients with and without rapid progression to CRPC within 24 months (P=0.02; Table 3), but not in the Gleason score (P=0.23) or initial PSA level (P=0.36).

Table 3. Association between ETS-1 expression and the time to CRPC in 25 metastatic prostate cancer patients treated by ADT.

Variable N Case No. in different group of time to CRPC P value
    >24 months <24 months  
ETS-1 expression (score)        
 0 10 7 3 0.02
 1 11 2 9  
 2 4 0 4  
Gleason score        
 6 or less 2 2 0 0.23
 7 8 2 6  
 8–10 15 5 10  
Initial PSA (ng ml−1)        
 <500 19 8 11 0.36
 >500 6 1 5  
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Abbreviations: ADT, androgen-deprivation therapy; CRPC, castration-resistant prostate cancer; ETS-1, E26 transformation-specific-1; PSA, prostate-specific antigen.

Discussion

In the present study, IHC staining showed that ETS-1 expression was localized to both the nucleus and cytoplasm, which is consistent with previous reports.11,12,13 The reliability of immunohistochemical techniques for the purpose of examining ETS-1 expression was supported by the well-correlated results of in situ hybridization.11,12 These collectively indicate that the IHC technique used in the present study is a reliable and reproducible method for evaluating the expression of functional ETS-1 protein.

Using this technique, we have demonstrated that ETS-1 expression is associated with clinical stage and the Gleason score of PCa. About 45% (13/29) of the PCa with no ETS-1 expression (staining score 0) were clinically localized tumors, whereas 83% (33/40) of those with higher expression (staining score 1–2) were advanced (Table 2). Additionally, all cases except one (97%) of those with higher ETS-1 expression contained a high-grade cancer component (Gleason score 7 or more). Our findings strongly suggest that ETS-1 expression is associated with the aggressive biological features of PCa, and therefore, associated with the adverse clinicopathological characteristics of PCa.

Additionally, we have shown that ETS-1 expression is significantly associated with the rapid castration-resistant progression of PCa after ADT. This is consistent with a previous report by Smith et al.19 showing that ETS-1 activation led PCa cells to a castration-resistant status. Our results suggest that ETS-1 expression can be a useful predictor for treatment outcome of patients with advanced PCa. A major clinical problem with hormonal therapy of advanced PCa is the pre-treatment prediction of time to castration-resistant progression.

Recently, Sim et al.21 reported that failure to attain a nadir PSA of <1 ng ml−1 after treatment was the most important predictor of time to CRPC and a nadir PSA of >2 ng ml−1 was a risk factor for poor overall survival. However, those findings will be obtained only after treatment has been initiated, and as the authors reported, prediction of treatment outcome at pre-treatment settings was difficult since the biopsy Gleason score or initial PSA level was not a predictor of rapid progression to CRPC. Indeed, the biopsy Gleason score and initial PSA level also failed to predict time to progression to CRPC in the present study. In this regard, a significant association between increased ETS-1 expression and a shorter time to CRPC observed in this study would enable us to separate those patients who are likely to fail on hormone therapy from those who are more likely to achieve long-term stable disease at pre-treatment settings. This is an important prospect, which should be validated with a larger study in the future. On the other hand, we did not observe a significant association between expression of ETS-1 and survival of patients with metastatic disease. Our interpretation is that although time to progress to CRPC is one of the determining factors of patient survival, there are several other factors that affect patient survival. In particular, recently, options for the treatment of CRPC patients have become available: for example, docetaxel. ETS-1 expression may be unrelated to response to docetaxel treatment. However, it is still important to predict time to progression to CRPC.

Aberrant activation of ETS family of transcription factors by gene fusion with certain androgen-dependent genes is a frequently observed alteration inducing invasion of PCa cells,22,23,24 which is now considered as an initiation25 and progression26 event in the natural history of PCa. Considering that members of the ETS family transcription factors share a number of target genes, ETS-1 is likely to play an important role in PCa. Indeed, a number of genes that can facilitate cancer progression are known as transcriptional target of ETS-1.7,10 Additionally, ETS-1 has been reported to activate transcription of Sp1 resulting in an increase in lipogenesis and cell proliferation through induction of fatty acid synthase,27 which is thought to be associated with castration-resistant progression of PCa.28 Moreover, considering less frequent ERG gene fusion in PCa patients in Asian population,24 impact of overexpression ETS-1 could be more significant in this ethnic group.

We recognize that this study has a limitation in that it followed relatively few patients, although its strengths included utilization of pre-treatment biopsy specimens of advanced PCa patients, comprehensive data collection, analysis by a central pathologist and a reasonable duration of follow-up, which helped to compensate for the small number of samples. Prospective validation studies on ETS-1 expression together with other molecular markers are warranted in the future. It would also be interesting to elucidate other biomarkers that are potentially related to ETS-1 expression or which strengthen the predictive accuracy for treatment responses of advanced PCa patients in future studies. In this regard, it would be interesting to know the correlation of PTEN status with ETS-1 expression, given the recent findings about the causal relationship of increased AKT activity and elevated ETS-1 expression in PCa cell lines.19 Using biopsy tissues can be problematic as tumors often exhibit heterogeneity; however, clinical decision-making is often based on biopsy specimens. Since our patients were relatively advanced, the value of ETS-1 expression was unclear in relatively early cases such as those with PSA levels <4.0 ng ml−1. It has been reported previously that the antibody used in this study can cross-react with Annexin V, an unrelated protein.29 Although we cannot strictly exclude the possibility that the antibody recognizes an unrelated protein, ETS-1 expression evaluated with the antibody still has diagnostic significance in predicting time to castration-resistant progression.

In conclusion, immunohistochemical analysis of PCa specimens clearly demonstrated that the expression of ETS-1 was associated with the pathological grade and clinical stage of the disease. Importantly, we found that ETS-1 expression was significantly associated with time to CRPC in patients with advanced PCa. Although further systematic studies are necessary, these findings support the possibility that a higher expression of ETS-1 can play an important role in the poor differentiation of PCa cells. Thus, ETS-1 may be a useful marker for the risk of PCa progression.

Author contributions

BL, YS and TK designed the experiments and BL and YS carried out the experiments. YS and YM evaluated the IHC. BL, TK, NT, KY, TK, TI and HN analyzed and discussed the data. HN and OO supervised the project. BL, YS and TK wrote the manuscript.

Acknowledgments

This study was partly supported by a grant-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Takeda Science Foundation (to B Li), and the Uehara Memorial Foundation (to T Kobayashi and O Ogawa).

All authors declare that there are no competing financial interests.

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