Signal Transducers and Activators of Transcription-3 Up-Regulates Tissue Inhibitor of Metalloproteinase-1 Expression and Decreases Invasiveness of Breast Cancer

Abstract

Signal transducers and activators of transcription (STAT)-3 is an oncogenic protein that is constitutively activated in many human cancers, including 30 to 60% of primary breast cancer. The biological significance of STAT3 activation in breast cancer is not fully understood. We have previously shown that STAT3 up-regulates tissue inhibitors of metalloproteinase (TIMP)-1, a cytokine known to block metalloproteinases and decrease invasiveness in certain cancer cell types. We hypothesize that STAT3 activation may modulate tumor invasiveness of breast cancer by regulating TIMP1 expression. Using MCF-7 cells transfected with tetracycline-off STAT3C (constitutively active STAT3), we generated an in vitro system in which STAT3C levels can be tightly controlled in breast cancer cells. Increasing tetracycline levels gradually decreased STAT3C and TIMP1 in a dose-dependent manner, and down-regulation of these proteins led to a reciprocal decrease in invasiveness of these cells in Matrigel. Addition of a neutralizing anti-TIMP1 antibody increased invasiveness in the same experimental system. Using immunohistochemistry and 142 primary breast tumors, we found a significant association between the expression of the phosphorylated/active form of STAT3 (pSTAT3) and that of TIMP1. Importantly, STAT3 activation correlated significantly with a lower frequency of vascular and lymphatic invasion (P ‫؍‬ 0.015 and P ‫؍‬ 0.0002, respectively). Our data support the concept that STAT3 activation significantly modulates the biological and clinical behavior of breast cancer.

Characterization and comparison of telomere length, telomerase and reverse transcriptase activity and gene expression in human mesenchymal stem cells and cancer cells of various origins

“…Interestingly, STAT3 is constitutively activated in ∼50%-60% of primary breast tumors and its downregulation decreases the tumorigenecity of breast cancer cells (Dien et al 2006). Moreover, recent loss-of-function studies have demonstrated OCT4 as an important mediator of some cancer cell phenotypes (Chang et al 2008) and NANOG as a biologically functional regulatory molecule in tumor development (Jeter et al 2009).…”

Upregulation of elastase proteins results in aortic dilatation in mucopolysaccharidosis I mice

“…Indeed, mRNA for IRF-8 and IRF-3 were increased in the ascending aorta of MPS I mice, and these proteins may function in a similar fashion on the cathepsin S promoter as IRF-1 [27]. In addition, TIMP-1 is regulated by STAT-3 [38], and its mRNA was 4-fold normal (Fig. 2).…”

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

“…Recent results from gene profiling analysis indicate that the expression signature of primary HCC is very similar to that of its corresponding metastases, suggesting that transcriptional changes which control metastatic progression are initiated in the primary tumors [251]. STAT3 however, is also known to upregulate tissue inhibitors of metalloproteinase TIMP-1, a cytokine known to block metalloproteinases and decrease invasiveness in certain cancer cell types [252]. STAT3 also controls the expression of the MUC1 gene, which can mediate tumor invasion [253].…”