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Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-ku, Nagoya 467-8601, Japan
¹ Breast and Endocrine Surgery, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan

(Requests for offprints should be addressed to H Yamashita; Email: hirokoy{at}med.nagoya-cu.ac.jp)

	Abstract

Top Abstract Introduction Patients and methods Results Discussion References

 
Constitutively activated signal transducers and activators of transcription (Stats), in particular Stat3 and Stat5, have been demonstrated to directly contribute to oncogenesis by stimulating cell proliferation and preventing apoptosis in various cancers. Stat3 is essential in mammary gland epithelial cell apoptosis and involution, whereas Stat5 is well established as a key factor in mammary epithelial cell growth and differentiation. Crosstalk between Stats and estrogen receptor (ER) has been demonstrated by several laboratories and we have focused on the role of Stat5 in ER-positive breast cancer. Using immunohistochemical techniques, we examined the expression of Stat3 and Stat5 in 517 human breast cancer tissues and analyzed their significance for prognosis and prediction of response to endocrine therapy. Stat5 expression was significantly correlated with histological grade (P < 0.0001), ER (P = 0.02), and progesterone receptor (P = 0.026) expression. There was no difference between Stat3 expression and clinicopathological factors. In 346 patients with ER-positive breast cancer, patients with Stat5 positive tumors had significantly increased overall survival (P = 0.0009) in multivariate analysis. There were 70 patients who received endocrine therapy as first-line treatment for metastatic breast cancer at relapse. The patients whose primary breast tumors were Stat5 positive, had significantly better response to endocrine therapy (P = 0.04), and longer survival after relapse (P = 0.0003), than those whose tumors were Stat5 negative. The present study demonstrates for the first time that Stat5 is a predictive factor for endocrine therapy response and a strong prognostic molecular marker in ER-positive breast cancer. Our data suggest that the expression of Stat5 is helpful in selecting patients who may benefit from endocrine therapy.

	Introduction

Top Abstract Introduction Patients and methods Results Discussion References

 
Signal transducers and activators of transcription (Stats) have been recognized as critical integrators of cytokine and growth factor receptor signaling required for cell growth, survival, differentiation, and motility. Stat3 is considered as an oncogene and also behaves as a tumor suppressor (Bromberg et al. 1999). Conditional knockout studies in mice have shown that Stat3 is essential in mammary gland epithelial cell apoptosis and involution (Chapman et al. 1999). Stat5 is also well established as a key factor in mammary epithelial cell growth and differentiation. Prolactin receptor-mediated signal transduction through the Jak2–Stat5 pathway is considered to be essential for proliferation and differentiation of normal mammary epithelial cells (Hennighausen et al. 1997, Watson 2001), and we have previously reported that Stat5a and Stat5b are phosphorylated on tyrosine and serine residues during mammary gland gestation and lactation (Yamashita et al. 2001).

Constitutively activated Stats, in particular Stat3 and Stat5, have been demonstrated to directly contribute to oncogenesis by stimulating cell proliferation and preventing apoptosis in various cancers. A role for Stat3 and Stat5 in the pathogenesis of human breast cancer is increasingly recognized. There is evidence of increased Stat binding in the nuclei of breast cancer compared with normal tissue of benign lesions (Watson & Miller 1995). An immunohistochemical (IHC) study of 62 cases of invasive breast cancers found that Stat3 was expressed only in the cytoplasm of non-tumor regions but was expressed in both the cytoplasm and nuclei of malignant regions (Berclaz et al. 2001, Dolled-Filhart et al. 2003). Another study assessed a microarray containing tissues from 346 node-negative breast cancer patients with both anti-Stat3 and anti-phospho-Stat3 IHC and found that nuclear phospho-Stat3 levels were correlated with better survival (Dolled-Filhart et al. 2003). Stat5 is also expressed and phosphorylated in human breast cancer (Nevalainen et al. 2002, Yamashita et al. 2003). IHC analysis of tissue microarray materials from more than 1300 breast cancers has found a strong association between Stat5 nuclear localization/phosphorylation and improved overall and disease-free survival (Nevalainen et al. 2004).

We have previously reported that Stat5b is constitutively activated in human breast cancer cells, and in vitro and in vivo overexpression of a dominant-negative variant of Stat5 in the estrogen receptor (ER)-positive breast cancer cell line T47D is associated with increased apoptosis (Yamashita et al. 2003, 2004a). Crosstalk between Stats and ER has been demonstrated by several laboratories (Stoecklin et al. 1999, Yamamoto et al. 2000, Faulds et al. 2001, Frasor et al. 2001, Bjornstrom & Sjoberg 2002a, Wang & Cheng 2004), and we have focused on the role of Stat5 in ER-positive breast cancer (Yamashita & Iwase 2002). In the present study, we examined the expression of Stat3 and Stat5 in 517 human breast cancer tissues and analyzed the significance for prognosis and prediction of response to endocrine therapy. Our results indicated that positive Stat5 expression is an independent prognostic marker of overall survival in ER-positive breast cancer. Furthermore, Stat5 expression in primary breast tumors was predictive of the response to endocrine therapy in metastatic breast cancer and patients with a positive expression of Stat5 had a significantly longer survival after relapse.

	Patients and methods

Top Abstract Introduction Patients and methods Results Discussion References

 
Patients and breast cancer tissues

Breast tumor specimens from 517 female patients with primary invasive breast carcinoma, who were treated at Nagoya City University Hospital between 1981 and 1999, were included in this study (Table 1). The study protocol was approved by the institutional review board and conformed to the guidelines of the 1975 Declaration of Helsinki. All patients had undergone surgical treatment with mastectomy or lumpectomy. After the surgery, 27% received no additional therapy. The remaining patients received systemic adjuvant therapy, 21% received endocrine therapy consisting of tamoxifen alone, 17% chemotherapy alone, and 35% of the total number of patients received a combined endocrine therapy and chemotherapy. Patients who were positive for axillary lymph nodes received either oral administration of 5-fluorouracil derivatives for 2 years or a combination of cyclophosphamide, methotrexate, and fluorouracil (CMF). Patients were observed for disease recurrence and death at least once every 6 months for 5 years after the surgery and once every year for more than 5 years after the surgery. The median follow-up period was 90 months (range, 2–273 months).

Immunohistochemical analysis for Stat3, Stat5, ER, PR, and HER2

One 4 µm section of each submitted paraffin block was first stained with hematoxylin and eosin to verify that an adequate number of invasive carcinoma cells were present and the fixation quality was sufficient for IHC analysis, as previously described (Yamashita et al. 2004b). Serial sections (4 µm) were prepared from selected blocks and float-mounted on adhesive-coated glass slides for Stat5, Stat3, ER, or PR staining. Primary antibodies included monoclonal mouse anti-Stat3 antibody (F-2, ImmunoCruz Staining System, Santa Cruz Biotechnology) for Stat3, monoclonal mouse anti-Stat5b antibody (G-2, ImmunoCruz Staining System, Santa Cruz Biotechnology) for Stat5, monoclonal mouse anti-human ER antibody (1D5, DAKO, Glostrup, Denmark) at 1:100 dilution for ER, monoclonal mouse anti-human PR antibody (636, DAKO) at 1:100 dilution for PR, and rabbit anti-human c-erbB-2 oncoprotein antibody (DAKO) at 1:200 dilution for HER2. The DAKO Envision system (DAKO EnVision labeled polymer, peroxidase) was used as the detection system for ER, PR, and HER2.

IHC scoring

Immunostained slides were scored after the entire slide was evaluated by light microscopy. The expression status of Stat3 and Stat5 was assessed according to the estimated proportion of staining in the cytoplasm or nuclei of tumor cells that were positively stained. Scoring criteria were as follows: score = 0, none; score = 1, < 1/10; score = 2, 1/10–1/2; score = 3, >1/2. Tumors with a score of 2 or greater were considered to be positive for Stat3 or Stat5 expression. The expression of ER and PR was scored by assigning a proportion score and an intensity score according to Allred’s procedure (Allred et al. 1998). In brief, a proportion score represented the estimated proportion of tumor cells staining positive, as follows: 0 (none); 1 ( < 1/100); 2 (1/100–1/10); 3 (1/10–1/3); 4 (1/3–2/3); and 5 (>2/3). Any brown nuclear staining in invasive breast epithelium counted towards the proportion score. An intensity score represented the average intensity of the positive cells, as follows: 0 (none); 1 (weak); 2 (intermediate); and 3 (strong). The proportion and intensity scores were then added to obtain a total score, which could range from 0 to 8. Tumors with a score of 3 or greater were considered to be positive for ER or PR expression. HER2 immunostaining was evaluated by the same method as the HercepTest (DAKO). To determine the score of HER2 expression, the membrane-staining pattern was estimated and scored on a scale of 0 to 3+. Tumors with a score 2 were considered to be positive for HER2 overexpression (Yamashita et al. 2004b).

Statistical analysis

The chi-square test was used to compare the IHC results of Stat3 and Stat5 with clinicopathological characteristics and response to endocrine therapy. Estimation of disease-free and overall survival was performed using the Kaplan–Meier method, and differences between survival curves were assessed with the log-rank test and the Breslow–Gehan–Wilcoxon test. Cox’s proportional hazards model was used for univariate and multivariate analyses of the prognostic values.

	Results

Top Abstract Introduction Patients and methods Results Discussion References

 
Immunohistochemical staining for expression of Stat3 and Stat5 in human breast tissues

To investigate the expression of Stat3 and Stat5 in human breast specimens, IHC analysis was performed (Fig. 1). IHC with specific antibodies for Stat3 (B) and Stat5 (E) showed the presence of cytoplasmic staining in invasive ductal carcinoma tissues. There were seven tumors that showed positive nuclear staining of Stat3 (C) and 18 tumors that showed positive nuclear staining of Stat5 (F). Cytoplasmic staining was also present in all tumors that showed positive nuclear staining of Stat3 or Stat5.

View larger version (141K): [in this window] [in a new window]   Figure 1 IHC staining for the expression of Stat3 and Stat5b in human breast tissues. (A) and (B), Expression of Stat3 in invasive ductal carcinoma. Negative (A) and positive (B) cytoplasmic staining is observed in carcinoma cells. (D) and (E), Expression of Stat5b in invasive ductal carcinoma. Negative (D) and positive (E) cytoplasmic staining was observed in carcinoma cells. (C) and (F), Positive nuclear staining for Stat3 (C) and Stat5b (F) is seen in carcinoma cells. Representative results are shown (magnification, 400x).

Of the 517 primary invasive carcinomas, 41.2% and 33.8% were positive for Stat3 and Stat5 expression respectively (Table 2). Stat5 expression was significantly correlated with histological grade (P < 0.0001), whereas no association was found between Stat5 expression and tumor size or number of positive lymph nodes. Positive associations were observed between Stat5 expression and ER (P = 0.02) and PR (P = 0.026) expression. There was no association between Stat3 expression and clinicopathological factors. Interestingly, Stat3 expression was strongly correlated with Stat5 expression (P < 0.0001) (Table 3). As there are many confounding factors that affect expression of Stat3 and Stat5, it is possible that the lack of association of Stat3 with clinicopathological features occurred despite the strong correlation between Stat3 and Stat5 expression.

Positive Stat5 expression was associated with increased overall survival in all patients (P = 0.065 by the log-rank test, P = 0.03 by the Breslow–Gehan–Wilcoxon test) (Fig. 2D), but not with disease-free survival (Fig. 2C). Stat3 expression status was not correlated with disease-free or overall survival (Fig. 2A and B). Importantly, in 346 patients with ER-positive breast cancer, Kaplan–Meier analysis of overall survival showed that positive Stat5 expression was correlated with significantly reduced risk of death (P = 0.02 by the log-rank test and P = 0.0026 by the Breslow–Gehan–Wilcoxon test) (Fig. 3B), although not with disease-free survival in these patients. Univariate analysis (Table 4) demonstrated that Stat5 expression (P = 0.02), as well as tumor size (P < 0.0001), lymph node status (P < 0.0001), and histological grade (P = 0.001), were strongly able to predict overall survival in ER-positive breast cancer. In multivariate analysis, patients with Stat5 positive tumors had significantly increased overall survival (P = 0.0009) (Table 4), indicating that Stat5 expression is an independent prognostic marker of overall survival in ER-positive breast cancer.

View larger version (14K): [in this window] [in a new window]   Figure 2 Effect of Stat3 expression on disease-free (A) and overall (B) survival among 506 patients with invasive carcinoma and effect of Stat5 expression on disease-free (C) and overall (D) survival among 510 patients with invasive carcinoma. Overall survival was significantly better in patients with Stat5 positive tumors than in patients with Stat5 negative tumors (P = 0.065) by the log-rank test (P = 0.03) by Breslow–Gehan–Wilcoxon test.

View larger version (11K): [in this window] [in a new window]   Figure 3 Effect of Stat5 expression on disease-free (A) and overall (B) survival among 346 patients with ER-positive breast cancer. Overall survival was significantly better in patients with Stat5 positive tumors than in patients with Stat5 negative tumors (P = 0.02) by the log-rank test and (P = 0.0026) by the Breslow–Gehan–Wilcoxon test).

There were 70 patients who received endocrine therapy as first-line treatment for metastatic breast cancer at relapse (Table 5). We analyzed whether expression of Stat3 and Stat5 in the primary breast tumors affected the response to endocrine therapy when given in this setting. Of the 70 invasive carcinomas, 37.1% and 27.1% were positive for Stat3 and Stat5 expression respectively, and 32 (45.7%) patients responded to the therapy (Table 6). Patients with primary breast tumors who had positive expression of Stat5 significantly responded to endocrine therapy (P = 0.04). Stat3 expression tended to affect response to the therapy (P = 0.07), but the association was not statistically significant.

We then analyzed whether expression of Stat3 and Stat5 in the primary breast tumors affected survival after relapse. The median follow-up period was 78 months (range, 5–234 months). Expression of Stat5 was associated with significantly increased post-relapse survival (P = 0.0003 by the log-rank test and P = 0.0065 by Breslow–Gehan–Wilcoxon test) (Fig. 4B), whereas Stat3 expression was unrelated to survival (Fig. 4A). Univariate analysis (Table 7) demonstrated significant correlations between post-relapse survival and expression of Stat5 (P = 0.001), as well as expression of ER (P = 0.003), PR (P = 0.0007), and HER2 (P = 0.006). We then selected expression of ER, HER2, and Stat5 for the multivariate analysis. Patients with positive Stat5 expression and negative HER2 overexpression had significantly increased post-relapse survival (P = 0.002 and P = 0.02 respectively), whereas ER expression was insignificant in the multivariate analysis (Table 7). We conclude that positive Stat5 expression is an independent prognostic marker of post-relapse survival in metastatic breast cancer patients who received first-line treatment with endocrine therapy on relapse.

View larger version (12K): [in this window] [in a new window]   Figure 4 Post-relapse survival of patients according to expression of Stat3 (A) and Stat5 (B) in primary tumors. Positive Stat5 expression was significantly associated with a better survival (P = 0.00031 by the log-rank test, P = 0.00652 by Breslow–Gehan–Wilcoxon test).

	Discussion

Top Abstract Introduction Patients and methods Results Discussion References

Stat family proteins are latent cytoplasmic transcription factors that convey signals from cytokine and growth factor receptors to the nucleus. When activated, cytoplasmic Stats are phosphorylated on a conserved tyrosine residue, translocate to the nucleus, and bind to target DNA. Positive nuclear staining of Stats by IHC indicates presence of phosphorylated Stats. There were a few tumors that showed positive nuclear staining of Stat3 or Stat5 in our analysis. Further study is needed to detect activated Stat proteins using specific antibodies for phosphorylated Stats.

Stat3 and Stat5 proteins are frequently overactivated in a variety of human solid tumors and blood malignancies (Yu & Jove 2004). Stat5 is considered as a survival factor for hematopoietic cells and has been implicated in the progression of leukemias. On the other hand, previous studies using mouse models suggested that Stat5 plays a critical role in lobuloalveolar proliferation, differentiation, and expansion, whereas Stat3 regulates lobuloalveolar apoptosis during pregnancy, lactation, and involution (Clevenger 2004). It was reported that there was a gradual loss of activation of Stat5 in human breast cancer as the tumors became more advanced, and that Stat5 activation in breast tumors was associated with favorable prognosis (Nevalainen et al. 2004). Another study of Stat5 in breast cancer demonstrated that nuclear-localized Stat5a was associated positively with increased levels of histologic differentiation (Cotarla et al. 2004). Consistent with these results, our study shows that positive Stat5 expression is strongly correlated with histological grade and better overall survival, especially in ER-positive breast cancer. In contrast, there was no association between Stat3 expression and clinicopathological factors. Further study is needed to evaluate phosphorylation of Stat3 and to analyze its role in breast cancer.

Both Stat3 and Stat5 have been reported to show crosstalk with ER signaling. We previously found that overexpression of a dominant-negative variant of Stat5 suppressed ER transcriptional activity and induced apoptosis in ER-positive breast cancer cells (Yamashita et al. 2003, 2004a), and we hypothesized that Stat5 had some role in ER-positive breast cancer (Yamashita & Iwase 2002). The most important results to come out of the present study concerned the correlation between clinical response and expression of Stat5. We have found that patients with primary breast tumors showing positive expression of Stat5 respond significantly better to endocrine therapy and have better post-relapse survival than those whose primary tumors were Stat5 negative. Our results suggest that co-expression of Stat5 and ER improves the effect of endocrine therapy. Although the mechanism underlying this is not clear, endocrine therapy might influence Stat5 signaling as well as ER signaling. In contrast, Stat3 expression seems to have little effect in ER-positive breast cancer.

Crosstalk between Stat5 and ER signaling pathways has been reported by several laboratories (Stoecklin et al. 1999, Faulds et al. 2001, Frasor et al. 2001, Bjornstrom & Sjoberg 2002a,b, Wang & Cheng 2004). ER and ERß have been demonstrated to act as coactivators for Stat5b through a mechanism which is independent of the activation function (AF)-1 and AF-2 (Bjornstrom et al. 2001). Our previous results demonstrated that overexpression of a dominant-negative variant of Stat5 suppresses ER transcriptional activity (Yamashita et al. 2003). Thus, Stat5 signaling also affects ER signaling pathways, and endocrine therapy may affect both Stat5 and ER signaling pathways.

Endocrine therapy has become the most important treatment option for women with ER-positive breast cancer. Nevertheless, many breast cancer patients with tumors expressing high levels of ER are unresponsive to endocrine therapy, and all patients with advanced disease eventually develop resistance to the therapy. The potential mechanisms behind intrinsic or acquired endocrine resistance involve ER-coregulatory proteins and crosstalk between the ER pathway and other growth factor signaling networks (Schiff et al. 2004, Osborne et al. 2005). Our results indicate for the first time that expression of Stat5 is a predictive factor for endocrine therapy and increases post-relapse survival in metastatic breast cancer patients who receive first-line treatment with endocrine therapy on relapse. An understanding of the molecular mechanisms that modulate the activity of estrogen-signaling network, including Stat5, will enable new ways of overcoming endocrine resistance.

In conclusion, the present study has demonstrated for the first time that Stat5 is a predictive factor for endocrine therapy and a strong prognostic molecular marker in ER-positive breast cancer. Our data suggest that expression of Stat5 is helpful in selecting patients who may benefit from endocrine therapy.

	Funding

 
This work was supported in part by Grants-in Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture in Japan 16591267. The authors declare that there is no conflict of interest that would prejudice the impartiality of this work.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Yamashita, H Articles by Iwase, H Search for Related Content PubMed PubMed Citation Articles by Yamashita, H Articles by Iwase, H