Abstract A17: Transforming growth factor beta stimulates STAT3 tyrosine phosphorylation and cellular invasion through interleukin‐6 in human breast cancer cell lines
2009
The signaling mechanisms involving Transforming Growth Factor β (TGFβ) and Signal Transducer and Activator of Transcription 3 (STAT3) are characterized in breast cancer, but the mechanism of crosstalk between these two pathways is poorly understood. In this study we addressed the question of TGFβ‐STAT3 cross‐signaling in nontransformed epithelial cells and in human breast cancer cell lines. Breast cancer continues to be a serious disease in the United States. A large component of novel chemotherapeutics specifically target overexpressed or overactivated proteins in cancers. Two examples of these oncogenic molecules are the cytokine TGFβ and the transcription factor STAT3. Although these proteins have each been implicated in early and late stages of cancer and invasion, the mechanism of cross‐talk between the TGFβ and STAT3 pathways has not been well characterized. We have observed that TGFβ treatment is sufficient to induce phosphorylation of STAT3 on its activating Tyr (705) site in nontransformed mouse mammary NMuMG epithelial cells. The time dependence of this relationship implies de novo expression of an intermediate factor that data suggest is Interleukin‐6 (IL‐6). TGFβ treatment induces gene upregulation of IL‐in a time‐dependent manner similar to that of TGFβ stimulated STAT3 tyrosine phosphorylation. Inhibition of IL‐6 with the mIL‐6 Receptor Fusion Protein Inhibitor (mIL‐6.RFPI) abrogated TGFβ stimulation of STAT3 tyrosine phosphorylation. Further, TGFβ treatment is sufficient to induce cellular invasion in NMuMG cells. This effect was recapitulated by IL‐6 treatment, while IL‐6 inhibition markedly reduced TGFβ stimulated invasion. The human breast cancer cell lines MDA‐MB‐231 and MDA‐MB‐361, which are basal‐like and luminal breast cancer models, respectively, display varying levels of constitutive STAT3 tyrosine phosphorylation. The MDA‐MB‐361 cell line exhibits no endogenous STAT3 phosphorylation but responds to TGFβ treatment in the same manner as nontransformed NMuMG mammary epithelial cells. Conversely, the MDA‐MB‐231 cell line displays high levels of constitutive STAT3 tyrosine phosphorylation, which data suggest is dependent in part on TGFβ signaling and is completely dependent on IL‐6 signaling. Taken together, interruption of the TGFβ‐IL‐6‐STAT3 signaling loop in MDA‐MB‐231 cells is sufficient to abrogate this signaling and dramatically reduce endogenous cellular invasiveness, while induction of the TGFβ‐IL‐6‐STAT3 pathway in MDA‐MB‐361 cells confers an invasive phenotype on this otherwise noninvasive cell line. Citation Information: Cancer Res 2009;69(23 Suppl):A17.
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