Journal
BREAST CANCER RESEARCH
Volume 9, Issue 3, Pages -Publisher
BIOMED CENTRAL LTD
DOI: 10.1186/bcr1680
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Funding
- NCI NIH HHS [R01 CA087637, R01CA87637] Funding Source: Medline
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Introduction 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. Methods 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. Results 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. Conclusion In summary, a principal mechanism of Stat3 activation in breast cancer is through the IL-6/gp130/Jak pathway.
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