Physiological and Pharmacological Regulation of the STAT3 Pathway in Cancer

STAT3 is a critical oncogenic transcription factor, but how it becomes aberrantly activated in cancer is unclear. We have discovered a new pathway whose loss is associated with persistent STAT3 activation in human cancer. We found that the tumor suppressor miR-146b is a direct STAT3 target gene in normal breast epithelial cells. However, STAT regulation of miR-146b is subverted in tumor cells and is suppressed by promoter methylation, which is increased in primary breast cancers. Moreover, we show that miR-146b inhibits NF-κB-dependent IL-6 production, IL-6-dependent STAT3 activation, and IL-6/STAT3-driven functional phenotypes, thereby establishing a negative feedback loop. In addition, miR-146b expression appears to be deregulated in tumors with the highest levels of activated STAT3, and is positively correlated with patient survival. Our results indicate a new mechanism of crosstalk between STAT3 and NF-κB relevant to constitutive STAT3 activation in malignancy and the role of inflammation in oncogenesis.