Transforming growth factor beta-induced tyrosine phosphorylation of signal transducer and activator of transcription 3 and cellular invasion is mediated by interleukin-6 secretion in breast cancer cell lines

A hallmark of breast cancers is the overexpression or constitutive activation of various oncoproteins. Two examples are the proteins Signal Transducer and Activator of Transcription 3 (STAT3) and Transforming Growth Factor beta (TGFbeta). Although each of these signaling molecules and their respective pathways have been implicated in cancer development, the mechanism of cross-signaling between these pathways has not been established in the cancer setting. We hypothesize that cross-talk between the TGFbeta and STAT3 pathways contributes to cancer invasiveness through an autocrine signaling loop.;Preliminary data in nontransformed mouse mammary NMuMG cells indicate that exogenous TGFbeta treatment results in phosphorylation of STAT3 on its activating Tyrosine (705) site. Strikingly, this effect is observed only after several hours of TGFbeta treatment and appears to be mediated by the cytokine Interleukin-6 (IL-6). TGFbeta induced IL-6 mRNA upregulation occurs concomitantly with TGFbeta-stimulated STAT3 tyrosine phosphorylation. Blockade of IL-6 function with a mouse IL-6 receptor fusion protein abrogates this effect, thereby implicating IL-6 as the factor responsible for TGFbeta-stimulated STAT3 tyrosine phosphorylation in NMuMG cells. TGFbeta confers an invasive phenotype on NMuMG and Mv1Lu cells that is IL-6 dependent.;Examination of this mechanism in human breast cancer cell lines suggests that TGFbeta-mediated secretion of IL-6 is responsible for the constitutive STAT3 tyrosine phosphorylation observed in many breast cancer cell lines. The invasive human MDA-MB-231 basal-like breast cancer cell line exhibits TGFbeta and IL-6 dependent invasion, while the noninvasive human MDA-MB-361 luminal breast cancer cell line is capable of attaining IL-6-dependent cellular invasiveness in response to TGFbeta treatment. (Full text of this dissertation may be available via the University of Florida Libraries web site. Please check http://www.uflib.ufl.edu/etd.html)...