Annals of Oncology Advance Access originally published online on January 10, 2006
Annals of Oncology 2006 17(4):597-604; doi:10.1093/annonc/mdj121
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© 2006 European Society for Medical Oncology
Survivin expression in breast cancer predicts clinical outcome and is associated with HER2, VEGF, urokinase plasminogen activator and PAI-1
1 School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland; 2 Division of Hematology-Oncology, Department of Medicine and 4 Department of Biomathematics and Biostatistics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA; 3 Departments of Obstetrics and Gynecology, Klinikum Grosshadern, Ludwig Maximilians Universität München, München, Germany; 5 Genentech, South San Francisco, California; 6 Department of Gynecologic Surgery, Mayo Clinic Foundation, Rochester, Minnesota; Departments of 7 Medical Oncology and 8 Nuclear Medicine and Medical Oncology, St Vincent's University Hospital, Dublin, Ireland
* Correspondence to: B. Ryan, Education and Research Centre, St Vincent's University Hospital, Dublin 4, Ireland. Tel: +353-1-209-4936; Fax: +353-1-283-8123; E-mail: Brid.Ryan{at}ucd.ie
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Abstract |
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Background: Survivin, a novel inhibitor of apoptosis, is one of the most cancer-specific proteins identified to date. In this study we (a) evaluated the association between survivin and HER2, vascular endothelial growth factor (VEGF) and uPA/PAI-1 expression and (b) defined its effect on clinical outcome in a large breast cancer patient cohort.
Patients and methods: Survivin expression was measured by ELISA in primary breast cancer tissue extracts from 420 patients with long-term clinical follow-up.
Results: Survivin was detected in 378 (90%) of the 420 primary breast cancer cases. Increased survivin levels were significantly associated with high nuclear grade (P < 0.0001), negative hormone receptor status (P = 0.0028), HER2 overexpression (P = 0.0094), VEGF expression (P < 0.0001), high uPA (P = 0.0002) and PAI-1 levels (P = 0.0002). Using the 25th percentile (1.4 ng/mg) as a cut-off point, patients expressing elevated survivin had a significantly worse disease-free survival (DFS: P = 0.0007, RR 1.97) and overall survival (OS: P = 0.0009, RR 2.11) compared with patients expressing lower levels of survivin. In multivariate analysis, this prognostic value of survivin was independent of both traditional and novel clinicopathologic factors for both DFS (P = 0.0076, RR 1.72) and OS (P = 0.0155, RR 1.76).
Conclusions: The independent prognostic relevance of survivin, when combined with previous data from model systems implicating survivin in the inhibition of apoptosis, suggests that survivin may be a suitable target for future therapeutic strategies.
Key words: breast cancer, HER2, prognosis, survivin, uPA/PAI-1, VEGF
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introduction |
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Survivin is a multifunctional protein implicated in control of cell proliferation [1
], inhibition of apoptosis [2] and the promotion of angiogenesis [3–5]. Survivin is notable for its high degree of tumor-specific expression, but is either undetectable or expressed at very low levels in differentiated adult tissues [2, 6]. Survivin is required for normal cell division and is involved in chromosomal segregation and cytokinesis [1]. In tumor cells, however, increased survivin expression can perturb normal cell cycle control and may, therefore, allow cells with spindle defects or aberrant chromosome assembly to proceed through cell division [7]. Furthermore, a pool of survivin that localizes to the mitochondria can block apoptosis in a cell cycle independent manner [8]. Increased expression of survivin correlates with poor clinical outcome in various malignancies, including hematologic [9], lung [10], colon [11], bladder [12], ovarian [13], endometrial [14] and prostate [15].
However, the role of survivin as a prognostic marker in breast cancer is controversial. Recent studies have reported its expression to be either prognostically irrelevant [16–18], associated with improved outcome [19] or associated with adverse outcome [20] in patients with breast cancer. To understand better the association between survivin expression and clinical outcome in primary breast cancer, we measured the absolute protein concentration of survivin by ELISA in the tumors of 420 primary breast cancer patients with long-term clinical follow-up. We further studied its association with other biological markers such as HER2 [21], vascular endothelial growth factor (VEGF) [22], urokinase plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor (PAI-1) [23, 24]. We then compared the prognostic significance of survivin with that of these newer biological markers.
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patients and methods |
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selection of patients
Breast cancer tissue specimens were obtained from a consecutive retrospective series of 420 patients treated for breast cancer at the Department of Obstetrics and Gynecology, University of Munich, Klinikum, Grosshadern between 1992 and 1997 (Table 1). The study cohort was originally used to prospectively evaluate the prognostic significance of uPA and PAI-1 in primary breast cancer, and has been described previously with a median patient follow-up of 26 months [25
]. In the current study, the median follow-up was extended to 69 months. Annotated clinical follow-up information was available for all of the patients. Patients underwent either modified radical mastectomy or lumpectomy with complete axillary lymph node dissection followed by radiation therapy of residual breast tissue. All of the lymph node-positive patients received adjuvant chemotherapy and/or tamoxifen therapy. Lymph node-negative patients received adjuvant chemotherapy and/or tamoxifen therapy, only if adverse prognostic factors were present such as large primary tumors (>2 cm), negative hormone receptor status, or elevated levels of either uPA or PAI-1. Criteria for exclusion from the study included distant metastasis at the time of diagnosis. Tumor samples and clinical information were obtained under Institutional Review Board approval.
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tissue extraction and measurement of survivin, HER2 and uPA/PAI-1 expression
Breast cancer tissue specimens were selected by the pathologist at the time of surgery and stored at –70°C until use. Frozen tissue samples of 100–200 mg were pulverized with a Microdismembrator (Braun-Melsungen, Melsungen, Germany) for 30 s at maximum power, suspended in 900 µl Tris-buffered saline (pH 8.5) containing 1% Triton® X-100 detergent (Sigma, Munich, Germany), incubated at 4°C for 12 h with gentle shaking, and then ultracentrifuged at 100 000 g for 45 min to remove cell debris, nuclei and membranes. Quantitative survivin protein levels were retrospectively measured in the supernatants with a commercially available ELISA kit (DuoSet IC ELISA, R and D Systems, Minneapolis, MN). Antigen concentrations for survivin were expressed as ng/mg protein.
Quantitative HER2 protein levels were measured in supernatants with a commercially available ELISA kit (Calbiochem San Diego, CA), as described earlier [25]. Antigen concentrations for HER2 were expressed as fmol/mg protein. As in previous studies, a cut-off value of 400 fmol/mg protein was used for HER2 overexpression [25].
uPA and PAI-1 protein levels were also measured in the supernatants, using ELISA (Imubind uPA and Imubind PAI-1; American Diagnostica, Stamford, CT), as previously described [23, 26]. Antigen concentrations for uPA and PAI-1 were expressed as ng/mg protein. The cut-off point for uPA and PAI-1 was 3 ng/mg of protein and 14 ng/mg of protein, respectively. These cut-off values were previously validated in a multicenter prospective randomized clinical trial investigating the prognostic value of uPA/PAI-1 in node-negative breast cancer patients [23]. For relating uPA and PAI-1 to clinical outcome, the two proteins were analyzed as one variable (both negative versus elevated uPA and/or PAI-1), as previous studies had shown that the combination of both markers gave a better risk-group discrimination than either alone [27].
tissue extraction and measurement of VEGF and hormone receptor expression
VEGF concentrations were retrospectively analyzed in tumor lysates routinely prepared for steroid hormone receptor measurements. Tissue samples (200–500 mg), collected at the same time as the samples used to measure survivin, HER2 and uPA/PAI-1, were homogenized with an Ultra-Turrax tissue disintegrator (Jahnke and Kunkel, Staufen, Germany) in 2–3 ml of buffer, containing 10 mM Tris, 0.1% monothioglycerol acetate and 1.5 mM EDTA (pH 7.4). The homogenate was then centrifuged for 30 min at 200 000 g at 4°C. VEGF was then measured in the resulting supernatant using an ELISA as previously described [28]. This assay detects all VEGF isoforms with 121 or more amino acids (VEGF121, VEGF145, VEGF165, VEGF183, VEGF189 and VEGF206). The assay also detects recombinant VEGF with amino acids 8–109, making it likely to detect VEGF110, a known plasmin digestion product of VEGF165 [29]. Antigen concentrations for VEGF were expressed as fmol/mg protein. The analytical sensitivity of the VEGF ELISA was 420 fmol/ml. Values below this detection limit were classified as VEGF-negative.
Assays for estrogen and progesterone receptor content were performed with enzyme immunoassays [ER-enzyme immunoassay (EIA) and PR-EIA; Abbott Laboratories, Chicago, IL], as described [30]. Antigen concentrations for estrogen and progesterone receptor expression were expressed as fmol/mg protein. The cut-off point for both ER and PR was 
10 fmol/mg protein.
statistical analysis
Associations between continuous variables were calculated by Spearman's correlation. Absolute levels of survivin were compared by the Wilcoxon rank sum test. The prognostic significance of survivin, HER2, uPA/PAI-1, VEGF and other clinical/pathological variables were determined using a univariate Cox model and the log rank statistic. Disease-free survival (DFS) and overall survival (OS) were used as end points. When testing survivin and VEGF as continuous variables, both were square-root transformed due to unequal variance. Survivin was also analyzed as a dichotomous variable using both the median and quartiles values as cut-off points. With the latter, level 1 
25th percentile, level 2 >25th and 50 percentiles, level 3 >50th and 75th percentiles, and level 4 >75th percentile. Level 1 was compared with levels 2–4 (>25th to >75th percentiles). The Wald test was used to determine whether the risk of DFS or OS varied depending on the survivin status of the tumor. The Wald statistic P value indicates the statistical significance of differences in odds ratios for a given risk factor, i.e. survivin.
Multivariate analysis was performed using multivariate Cox regression. The following variables were also studied: age and VEGF levels as continuous variables; nuclear grade (1, 2 versus 3, 4); hormone receptor status [estrogen receptor (ER) and/or progesterone receptor (PR)-positive versus ER- and PR-negative]; axillary lymph node status (positive versus negative), HER2 status (positive versus negative, <400 versus 400 fmol/mg protein); and uPA/PAI-1-negative (uPA <3 ng/mg protein and PAI-1 <14 ng/mg protein) versus uPA/PAI-1-positive (uPA >3 ng/mg protein and/or PAI-1 >14 ng/mg protein). Statistical calculations were performed using SAS (SAS, Inc., Cary, NC) software. All of the tests of statistical significance were two-sided. P values <0.05 were regarded as statistically significant.
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results |
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association between survivin and tumor characteristics
Survivin protein was detected in 378/420 (90%) i.e.
1 ng/mg protein of breast cancer tissue extracts. Median survivin levels were 4.5 ng/mg protein, while the range was 0.4–125 ng/mg protein. Table 2 summarizes the associations between survivin levels and tumor characteristics. Increased survivin expression was significantly associated with high nuclear grade (P < 0.0001), nodal positivity (P < 0.0171), ductal compared to non-ductal histology (P = 0.0049), HER2 overexpression (P = 0.0094), detectable VEGF expression (P < 0.0001), high uPA expression (P = 0.0002), high PAI-1 expression (P = 0.0002), negative estrogen receptor status (P = 0.0028) and negative progesterone receptor status (P = 0.0005). Using Spearman Correlation analysis, absolute survivin levels correlated significantly, but weakly, with those of VEGF (r = 0.22, P < 0.0001, n = 379), uPA (r = 0.22, P < 0.0001, n = 419) and PAI-1 (r = 0.24, P < 0.0001, n = 419), but not with HER2 levels, patient age or tumor size.
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association between survivin and patient outcome using univariate analysis
Initially, survivin was analyzed for prognostic value as a continuous variable. Increasing survivin protein levels were significantly associated with poor DFS [Wald test, P = 0.003; relative risk (RR), 1.12; 95% confidence interval (CI) 1.04 –1.20] and shortened OS (Wald test, P = 0.0035; RR 1.13; 95% CI 1.04–1.22). Then, to explore further the prognostic utility of survivin, and because a biologically relevant cut-off value for survivin protein was not known, we categorized its expression levels using both the median (4.5 ng/mg) and quartile values (25th percentile, 1.4 ng/mg; 50th percentile, 4.5 ng/mg and 75th percentile, 11.3 ng/mg) as cut-off points. Using the median value as a cut-off point, patients with high levels of survivin protein expression had a significantly worse DFS (Wald test, P = 0.0109, RR 1.47; 95% CI 1.09–1.99) and OS (Wald test, P = 0.0138, RR 1.51; 95% CI 1.09–2.10) compared with patients with lower levels of survivin (Figures 1A and 2A). Similarly, using the 25th percentile as a cut-off point, patients with elevated survivin levels had a worse outcome than those with low levels, i.e. levels 2, 3, 4 versus level 1 (DFS: Wald test, P = 0.0007, RR 1.97, 95% CI 1.33–2.90; and OS: Wald test, P = 0.0009, RR 2.11, 95% CI 1.36–3.27) (Figures 1B and 2B). Kaplan–Meier curves for DFS, using median and quartile values as cut-off points, are shown in Figures 1A and 1B, respectively. Similar curves for OS are shown in Figures 2A and 2B, respectively. It is clear from Figures 1B and 2B, which illustrate the quartile values as cut-off points for DFS and OS, that patients with levels of survivin in quartile 1, i.e.
1.4 ng/mg, had a particularly favorable outcome compared with patients with survivin levels >1.4 ng/mg. The differences in outcome between the remaining groups were less pronounced.
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Other factors that predicted outcome for either DFS or OS using univariate analysis included patient age, tumor size, lymph node status, nuclear grade, hormone receptor status, HER2 and uPA/PAI-1 (Table 3). Increasing VEGF levels tended to associate with poor OS, although the difference did not reach statistical significance (Wald test, P = 0.079, RR 1.04, 95% CI 0.99–1.08).
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association between survivin and patient outcome using multivariate analysis
For multivariate analysis, the following variables were included in the model: age, tumor stage, lymph node status, hormone receptor status, nuclear grade, histology, HER2 status, uPA/PAI-1 status, VEGF and survivin expression. As shown in Table 4, when survivin was analyzed as a continuous variable, it retained prognostic significance for DFS (Wald test, P = 0.0438, RR 1.09, 95% CI 1.00–1.18), but not for OS. However, using the 25th percentile as a cut-off, survivin was an independent prognostic factor for both DFS (Wald test, P = 0.0076, RR 1.72, 95% CI 1.16–2.56) and OS (Wald test, P = 0.0155, RR 1.76, 95% CI 1.11–2.79).
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On the other hand, survivin was not an independent prognostic factor for either DFS or OS when the median value was used as a cut-off point. Other factors that did retain prognostic significance in multivariate analysis included nodal status, hormone receptor status and HER2 status (with DFS as the end point), and age, nodal status, hormone receptor status and uPA/PAI-1 status (with OS as the end point) (Table 4).
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discussion |
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This is the largest study to date to investigate survivin expression in breast cancer, and the first to utilize a quantitative assay, i.e. an ELISA. Furthermore, it is the first study in breast cancer to relate survivin expression to HER2, VEGF and uPA/PAI-1. Our results show that survivin expression was significantly associated with the presence of lymph node metastases, high tumor grade, HER2 overexpression, high VEGF expression, high levels of uPA and high levels of PAI-1. On the other hand, an inverse relationship was found between survivin expression and hormone receptor status. In contrast to our findings, other investigators who used either immunohistochemistry [16
, 19] or conventional PCR [17] to determine survivin expression failed to find a significant association between survivin and tumor grade, lymph node status or estrogen receptor status in breast cancer. Consistent with our findings however, Span et al. [20], who used real-time PCR to determine quantitative survivin mRNA levels, also found a relationship between survivin expression and both high tumor grade and hormone receptor-negativity.
These findings suggest that the use of sensitive and quantitative assays, such as ELISA or real-time PCR, may provide more reliable data for survivin than the use of less sensitive and semi-quantitative methods such as immunohistochemistry or conventional PCR. It is of interest that in sarcomas, Kappler et al. [31], using the same ELISA as described in this study, found a significant correlation between survivin levels as determined by ELISA and tumor grade. However, no such relationship was found when survivin was detected with the semi-quantitative method of Western blotting. Similarly, the prognostic value of survivin in sarcomas was stronger when determined by ELISA as opposed to Western blotting [31].
Our finding of a significant relationship between survivin and HER2 overexpression in primary breast tumors has also been observed by Chu et al. [18]. The anti-apoptotic effects of HER2 were shown to be mediated by signaling through the phosphatidylinositol-3-kinase (PI3-K)/AKT pathway [32]. Indeed, signaling via PI3-K/AKT was previously shown to up-regulate survivin expression [33–35]. Thus, it is possible that HER2, by acting through the PI3-K/AKT pathway, may block apoptosis by up-regulating expression of survivin.
The anti-apoptotic effect of survivin is not confined to tumor cells, as it can also be manifested in endothelial cells potentially enhancing angiogenesis [4, 5, 36]. In cultured endothelial cells, VEGF was shown to up-regulate survivin expression [3, 4]. Furthermore, this up-regulation of survivin was found to play a pivotal role in VEGF-mediated endothelial cell protection by preserving the microtubule structure [4]. Survivin was subsequently found to enhance tumor angiogenesis in vivo [4]. Our finding here of a significant correlation between survivin and VEGF levels is consistent with the coordinated regulation of expression of these two proteins in breast cancer.
In addition to the correlation with HER2 and VEGF, survivin levels were also significantly related to those of uPA and PAI-1. uPA is a serine protease implicated in extracellular matrix remodeling, cell motility, cell proliferation and metastasis (see [37] for review). PAI-1, although an inhibitor of uPA, has also been shown to play a role in metastasis, perhaps by regulating cell migration and cell adhesion [37]. In lymph node-negative breast cancer patients, the prognostic impact of uPA/PAI-1 has been validated using both a randomized prospective trial and a pooled analysis of raw data from 18 independent data-sets [23, 24]. Why survivin correlates with uPA and PAI-1 levels is not clear. It may, however, relate to the existence of factors that up-regulate expression of all three genes.
Although not investigated in this study, survivin was previously related to both pro- and anti-apoptotic factors in breast cancer. For example, two studies found no association between survivin and p53 protein [16, 38]. In contrast, Tsuji et al. [39] reported that survivin correlated with the presence of p53 gene mutations in breast cancer. This finding is consistent with the recent report showing a negative regulation of survivin by p53 [40, 41]. In other studies, survivin expression in breast cancer was found to correlate with bcl-2 [16, 18, 38] and bak [18]. No correlation however, was detected between survivin and bax [18, 38].
Our results showing a positive association between survivin levels and indices of poor prognosis (i.e. nodal metastases, high tumor grade, hormone receptor-negativity, overexpression of HER2, expression of VEGF and high levels of uPA and PAI-1), when combined with previous data from model systems implicating survivin in the inhibition of apoptosis, control of cell division and promotion of angiogenesis [42], suggests that high expression of this anti-apoptotic protein should be associated with adverse outcome in patients with breast cancer. As shown in Tables 3 and 4, elevated levels of survivin were indeed correlated with both a shortened disease-free and overall survival. Importantly, using the 25th percentile as a cut-off point, survivin was an independent prognostic factor for DFS and OS, i.e. it was independent of not only traditional clinicopathologic factors, but also of the newer biological factors such as HER2, VEGF and uPA/PAI-1.
Previously, Kennedy et al. [19] reported that high levels of nuclear survivin, as determined by immunohistochemistry, predicted good outcome in patients with breast cancer. The antibody used in their study was capable of detecting the 
Ex3 splice variant of survivin, a form of survivin that appears to be located mostly in the nucleus [43]. The ELISA used in this study is likely to have detected both the nuclear and cytoplasmic forms of survivin. However, as the cytoplasmic form is the predominant cellular species of survivin [44], our assay would have detected mostly this form. Consistent with our findings, Span et al. [20] found that increased survivin mRNA expression was associated with adverse outcome in patients with primary breast cancer.
In addition to its potential prognostic value, survivin may also be a predictor of therapeutic efficacy. It is now believed that most anti-cancer therapies induce tumor regression, at least in part, by mediating apoptosis. As survivin is an inhibitor of apoptosis, high tumor levels might be expected to confer resistance to treatments that act by mediating this form of cell death. Evidence supporting such a hypothesis has been obtained from studies that manipulated the concentration of survivin in several cell lines. For example, transfection of ovarian cancer cells with survivin cDNA resulted in resistance to taxanes [45]. Conversely, decreasing survivin expression was found to increase sensitivity to etoposide [46], 5-FU [47] and radiotherapy [48].
Finally, as survivin is highly up-regulated in malignancy and is involved in the critical determinants of tumor progression such as evasion of apoptosis, increased proliferation and angiogenesis, it is an attractive target for new anti-cancer therapies (reviewed in [42]). Indeed, targeting survivin in preclinical models has already provided promising results. Strategies currently being investigated include: (a) the induction of an antigen-specific immune response against survivin-expressing malignant cells [49, 50], (b) the use of antagonists such as antisense oligonucleotides, ribozymes and dominant negative mutants [51] and (c) pharmacological inhibition of phosphorylation of survivin at Thr34 [52]. A particularly attractive feature of targeting survivin is that its inactivation should result in both tumor cell apoptosis and suppression of angiogenesis. Indeed, in a recent study on a mouse model, Xiang et al. [53] showed that the administration of an oral vaccine against survivin and the secretory chemokine CCL21 induced a T-cell mediated anti-tumor response against established pulmonary metastases from non-small-cell lung cancer. This anti-tumor response, involving the suppression of tumor angiogenesis and the induction of tumor cell apoptosis, was sufficient to cause their ablation.
In conclusion, survivin, like ER and HER2, is a potentially important prognostic marker in breast cancer. In addition, it has potential as a predictive marker and as a target for anti-cancer therapies. Such therapies directed against survivin would be expected to have the greatest effect in those tumors expressing high levels of survivin. The ELISA described in this study is a sensitive and quantitative method for determining survivin expression.
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Acknowledgements |
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Supported in part by the Revlon/UCLA Women's Cancer Research Program, DAMD17-01–1–0181 (MDP), the Irish Research Council for Science Engineering and Technology and the Health Research Board of Ireland. The current study was presented in part at the annual meeting of the American Society of Clinical Oncology, Orlando, 2005.
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Notes |
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BMR and GEK contributed equally to this work.
Received for publication September 12, 2005. Revision received November 28, 2005. Accepted for publication November 30, 2005.
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