Stat3 is tyrosine-phosphorylated through the interleukin-6/glycoprotein 130/Janus kinase pathway in breast cancer
- Marjan Berishaj†1,
- Sizhi Paul Gao†1,
- Simi Ahmed†2,
- Kenneth Leslie1,
- Hikmat Al-Ahmadie3,
- William L Gerald3,
- William Bornmann4 and
- Jacqueline F Bromberg1Email author
© Berishaj et al.; licensee BioMed Central Ltd. 2007
Received: 29 March 2007
Accepted: 25 May 2007
Published: 25 May 2007
Signal transducer and activator of transcription 3 (Stat3) is constitutively tyrosine-phosphorylated in approximately 50% of primary breast carcinomas. A number of different mechanisms responsible for Stat3 activation, including abnormal activation of receptor tyrosine kinases, Src, and Janus kinases (Jaks), have been implicated in breast cancer.
We examined six breast cancer-derived cell lines expressing high or low levels of tyrosine-phosphorylated Stat3 (pStat3) as well as primary breast cancer specimens.
Inhibition of Src or EGFR (epidermal growth factor receptor) tyrosine kinases had no effect on pStat3 levels, whereas pan-Jak inhibitor P6 resulted in complete abrogation of Stat3 phosphorylation and inhibition of growth. Jaks are required for cytokine signaling, and the glycoprotein 130 (gp130) receptor-associated Jaks are known mediators of Stat3 phosphorylation. Blockade of the gp130 receptor or sequestration of the interleukin-6 (IL-6) ligand led to a decrease of pStat3 levels. Conditioned media from those cell lines expressing high levels of pStat3 contained IL-6 and were capable of stimulating Stat3 phosphorylation. We examined IL-6 levels in primary breast tumors and found a positive correlation between pStat3 and IL-6 expression.
In summary, a principal mechanism of Stat3 activation in breast cancer is through the IL-6/gp130/Jak pathway.
The Stat (signal transducer and activator of transcription) family of proteins are transcription factors known for their role as integrators of cytokine and growth factor receptor signaling and are required for cell growth, survival, differentiation, and motility [1, 2]. Stat activation is dependent upon tyrosine phosphorylation, which induces dimerization via reciprocal phosphotyrosine-SH2 (Src homology domain 2) interaction between two Stat molecules. Activated Stats translocate to the nucleus, where they bind to consensus promoter sequences of target genes and activate their transcription . In normal non-transformed cells, Stat tyrosine phosphorylation is transient. However, in numerous cancer-derived cell lines and in an ever-growing number of primary tumors, Stat proteins (in particular, Stat3) are persistently tyrosine-phosphorylated .
Stat3 is constitutively activated in more than 50% of primary breast tumors and tumor-derived cell lines [5–17]. Clinical studies demonstrated that elevated levels of tyrosine-phosphorylated Stat3 (pStat3) in patients with stage II breast cancer correlated with an incomplete response to neo-adjuvant chemotherapy (a poor prognostic feature) . The evidence that activated Stat3 participates in a causal manner in breast tumorigenesis is based on studies from cell lines expressing high levels of pStat3. Inhibiting or removing Stat3 leads to increased apoptosis, chemosensitivity, and decreased angiogenesis both in cell culture and in xenograft models [5, 6, 10, 13, 14, 18–22]. Furthermore, the expression of a constitutively active form of Stat3 (Stat3C) into immortalized human breast epithelial cells mediated de novo tumorigenesis, demonstrating the sufficiency of this transcription factor in promoting cellular transformation . Stat3 activation can occur through the actions of many autocrine and paracrine growth factors (for example, interleukin-6 [IL-6], epidermal growth factor, platelet-derived growth factor, heregulin, vascular endothelial growth factor, and hepatocyte growth factor) and the Src non-receptor tyrosine kinase, leading to the prediction that its phosphorylation in breast cancer would be through these multiple, redundantly acting growth factors [6–8, 12, 13, 18, 19, 23–25]. Among these candidate cytokines, IL-6, which activates Stat3 through the glycoprotein 130/Janus kinase (gp130/Jak) pathway, is notable for its pleiotropic tumor-promoting activities, including anti-apoptotic, pro-invasive, and immune-stimulatory effects attributable to the activation of Stat3 target genes [26, 27]. Furthermore, high IL-6 levels have been linked to a poor prognosis in patients with advanced breast cancer, the pathogenesis of inflammatory breast cancer, and resistance to chemotherapy . Our studies have revealed a prominent and non-redundant role for IL-6 in driving Stat3 activation in breast cancer.
Materials and methods
MCF7, BT-474, MDA-MB-435, MDA-MB-468, MDA-MB-231, and MCF10A cells were purchased from the American Type Culture Collection (Manassas, VA, USA) and grown in Dulbecco's modified Eagle's medium supplemented with penicillin/streptomycin (Invitrogen Corporation, Carlsbad, CA, USA) and 10% fetal bovine serum. MCF10A cells were cultured as described previously . The 4175 metastatic subline of MDA-MB-231 cells was a gift from Joan Massague (Memorial Sloan-Kettering Cancer Center [MSKCC], New York, NY, USA) and was cultured as previously described . Cell proliferation was determined using an MTT (3- [4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay (as described by the vendor) with a microplate reader (Sigma-Aldrich, St. Louis, MO, USA).
Multitissue blocks of formalin-fixed, paraffin-embedded breast cancer tissue (containing three or four representative 0.6-mm cores) were prepared using a tissue arrayer, and immunohistochemistry (IHC) was performed as described [16, 30]. Antigen retrieval using citric acid (pH 6.0) at 97°C for 30 minutes was followed by treatment with 3% H2O2. Phospho-Stat3 (Tyr-705) (Cell Signaling Technology, Inc., Danvers, MA, USA) was used at 1:200. Anti-human IL-6 goat polyclonal antibody (R&D Systems, Inc., Minneapolis, MN, USA) was used at a 1:100 dilution . Anti-human estrogen receptor (ER) antibody (Immunotech, now part of Beckman Coulter, Fullerton, CA, USA) anti-human progesterone receptor (PR) antibody (BioGenex, San Ramon, CA, USA), and anti-Her2neu antibody (CB11; Dako North America, Inc., Carpinteria, CA, USA) were used at a 1:200 dilution. pStat3 positivity was defined as 3+, 2+, 1+, or 0 by IHC. Her2 positivity was defined as 3+ by IHC or as 2+ by IHC with a gene amplification of 2.1 or greater . For ER and PR, samples were considered positive if more than 10% of cell nuclei were immunoreactive. Scoring of the tissue microarray was performed by two independent observers (JFB and MB) with a high correlation between scorers (p < 0.001) for both pStat3 and IL-6. For a tumor to be considered positive for either pStat3 or IL-6, all four replicates in the tissue array had to have a similar staining intensity; otherwise, the tumor was excluded. Statistical analyses were performed using STATVIEW (SAS Institute Inc., Cary, NC, USA). The correlation between the scores of both scorers and the relationship between that of pStat3 and IL-6, ER, PR, and Her2neu were measured using the χ2 test.
Enzyme-linked immunosorbent assay
Cells were grown to approximately 50% to 85% confluence, and conditioned media (CM) was analyzed for IL-6 by means of an IL-6 enzyme-linked immunosorbent assay (ELISA) kit (Cell Sciences, Inc., Canton, MA, USA) according to the manufacturer's instructions.
Western blot and antibodies
Whole-cell, nuclear, and cytoplasmic extracts were prepared as previously described . Protein concentration was determined using the Bradford assay (Bio-Rad Laboratories, Inc., Hercules, CA, USA), and Western blot analysis was carried out by standard methods. Antibodies for Western blotting included Stat3, pStat3, Src, and pSrc (Cell Signaling Technology, Inc.). Phosphorylated Jak2 and Jak2 antibodies were obtained from Calbiochem (San Diego, CA, USA) and Upstate (now part of Millipore Corporation, Billerica, MA, USA), respectively. Gp130-blocking antibody, BR-3, and IL-6-blocking antibody, 522, were obtained from Cell Sciences, Inc. Leukemia inhibitory factor (LIF)-blocking and oncostatin M (OSM)-blocking antibodies were purchased from R&D Systems, Inc.
Tetracyclic pyridone 2-tert-butyl-9-fluoro-3,6-dihydro-7H-benz [h]-imidaz [4,5-f]isoquinoline-7-one, P6, was synthesized by author WB . Gefitinib (ZD) was a gift from AstraZeneca (London, UK) provided by Jackie She from the Anti-Tumor Assessment Core Facility, MSKCC. Dasatinib (BMS-354825) was synthesized by Darren Veach at MSKCC.
Stat3 is tyrosine-phosphorylated in approximately 50% of primary breast tumors
Immunohistochemical analysis of 85 primary breast tumors for pStat3, interleukin-6, estrogen receptor, progesterone receptor, and Her2neu
pStat3 0, 1+ (54%)
pStat3 2, 3+ (46%)
P value (Fisher)
Interleukin-6 (2, 3+)
Interleukin-6 (0, 1+)
Her2neu (2, 3+)
Her2neu (0, 1+)
Stat3 is constitutively tyrosine-phosphorylated in breast cancer-derived cell lines
Stat3 phosphorylation is blocked by Jak kinase inhibition but not Src or epidermal growth factor receptor blockade
Gp130 and IL-6 blockade inhibits Stat3 activation in breast cancer-derived cell lines
High IL-6 and pStat3 levels positively correlate in primary breast cancer
By using animals deficient for Stat3 in certain tissues or by introducing dominant negative Stat3 constructs and anti-sense and short hairpin RNA Stat3 molecules into cell lines, many investigators have demonstrated a requirement for Stat3 in tumorigenesis . Thus, inhibiting Stat3 activity or expression is likely to be an important therapeutic modality for a number of malignancies, including breast cancer. Targeting the Stat3 molecule directly is of significant interest, and indeed several small molecules that appear to target the Stat3 SH2 domain or the DNA-binding capacity of Stat3 have been developed [43–45]. It has been assumed that the kinases responsible for Stat3 activation are many, and therefore targeting one kinase or receptor would not be of benefit for the treatment of a variety of tumors.
Here, we examined the mechanisms of Stat3 phosphorylation in breast cancer. We observed that high pStat3 levels in primary tumor specimens did not correlate with nuclear hormone receptor status (ER or PR) nor overexpression of the Her2neu receptor (Table 1). It has been suggested in murine models of breast cancer that aberrant Her2neu signaling may mediate Stat3 activation . However, in primary human breast tumors, no such relationship was observed [7, 11, 17]. We examined pSrc and pEGFR levels by IHC in these tumor specimens, but less than 3% of the samples had elevated expression of these proteins, possibly for technical reasons as these values appear to be too low compared to other reports (data not shown) [7, 8]. To examine the potential mechanisms involved in mediating Stat3 phosphorylation, we examined breast cancer-derived cell lines expressing high levels of pStat3. Inhibition of EGFR and Src kinases did not have an effect on pStat3, suggesting that these kinases are not direct mediators of Stat3 phosphorylation in these breast cancer-derived cell lines. Our data regarding Src inhibition differ from those described by Garcia and colleagues  whereby treatment of MDA-MB-468 cells with an Src inhibitor (PD180970) resulted in inhibition of pStat3. Similarly, it was reported that treatment of MDA-MB-231 cells with an EGFR inhibitor (AG1478) inhibited Stat3 activation . In our study, we used different inhibitors of both Src and EGFR at concentrations previously described to potently inhibit both of these kinases. The explanations for these discrepancies are not clear, but differences in inhibitor selectivity and the length of time for which cells are treated could explain our differing observations. Interestingly, dasatinib treatment of both lung and prostate cancer-derived cell lines did not affect pStat3 levels, suggesting that Src inhibition does not play a role in mediating Stat3 activation in these cancer-derived cell lines [38, 39]. In contrast to EGFR and Src inhibition, a pan-Jak inhibitor inhibited pJak2 and Stat3 phosphorylation (Figure 3). Furthermore, treatment of the cell lines with an anti-gp130 antibody significantly inhibited Stat3 phosphorylation (Figure 4). Given the previously described association between the EGFR family members and gp130 receptor, we attempted but were unable to show any physical association between EGFR and gp130 by immunoprecipitation experiments in MDA-MB-468 cells (which express the highest levels of EGFR) (data not shown) .
The cytokine receptor gp130 is the common signaling subunit for the IL-6 family of cytokines. The gp130 receptor is ubiquitously expressed in tissues and mediates numerous homeostatic functions, including immune response, inflammation, bone metabolism, and hematopoiesis . IL-6, IL-11, OSM, LIF, and ciliary neurotropic factor are among the IL-6 family cytokines that use and require gp130 as a signaling subunit . We determined that IL-6 was the essential cytokine mediating gp130 activation in MDA-MB-468 and MDA-MB-231 cells and the 4175 subline (Figure 4). We did not observe inhibition of pStat3 by the IL-6-blocking antibody in the MDA-MB-435 cell line nor was IL-6, LIF, or OSM detected in the CM from this cell line. We believe that IL-11 is responsible for mediating Stat3 activation because IL-11 mRNA levels were increased in this cell line compared to MDA-MB-468 cells (data not shown). However, we have yet to confirm by immunological means that IL-11 is mediating gp130 activation.
The data presented here suggest that the principal mediator of Stat3 activation in breast cancer is through the IL-6 family of cytokines activating the gp130/Jak signaling pathway. Stat3 activation through the gp130 receptor is regulated by both positive effectors such as IL-6 and negative regulators, including suppressor of cytokine signaling (SOCS) 1 and SOCS3, which inhibit Jak activity . SOCS1 and SOCS3 promoters are frequently methylated in primary tumors and cancer-derived cell lines, resulting in decreased expression of these negative regulators of Jaks and leading to sustained Jak activation . We hypothesize that even in the absence of IL-6 or IL-6 engagement with the gp130 receptor, Jaks may still be activated due to the lack of SOCS gene expression and can only be fully inhibited with a Jak inhibitor.
To directly examine the singular importance of IL-6 as the activator of Stat3 in breast cancer, pStat3 levels and IL-6 levels were compared by IHC analysis of 82 primary breast cancer specimens and a significant positive correlation was observed between high pStat3 and high IL-6 levels as determined by IHC (p < 0.001). We also examined levels of gp130 and were unable to obtain consistent immunohistochemical data (data not shown).
We propose that the IL-6/gp130/Jak signaling pathway plays a critical role in Stat3 activation in human breast cancer and that blockade of this pathway may be an important therapeutic modality in breast cancer.
epidermal growth factor receptor
enzyme-linked immunosorbent assay
leukemia inhibitory factor
Memorial Sloan-Kettering Cancer Center
tyrosine-phosphorylated signal transducer and activator of transcription 3
Src homology domain 2
suppressor of cytokine signaling
signal transducer and activator of transcription 3.
This study was supported by National Institutes of Health grant R01 CA87637 and the Patrick M. Byrne Grant, by grants from the Sussman Family Fund, the Charles and Marjorie Holloway Foundation, and the Breast Cancer Alliance, by Lerner and Leigh Awards to JFB, and by New York State Department of Health (New York State Breast Cancer Research and Education Fund) grant C021338 to SPG. The opinions expressed are solely those of the authors and do not necessarily reflect those of the New York State Department of Health or the State of New York. SA was supported by a Cancer Research Institute Postdoctoral Award. We thank Darren Veach and Bayard Clarkson for synthesizing BMS-354825. We are grateful for the help of Marina Asher for immunohistochemical analysis. This manuscript was written in memory of Stella Faicco.
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