Transcription Factor STAT3 As a Prognostic Marker and Therapeutic Target in Cancer

In the early 1990s, researchers identified a mechanism by which cytokines interacting with cell surface receptors could modulate gene expression in the nucleus. Using elegant genetic and molecular approaches, it was found that activation of these receptors leads to phosphorylation of a family of proteins now called STATs that then shuttle into the nucleus, bind to specific sequences in the regulatory region of target genes, and alter their expression (Fig 1). STAT3, in particular, was found to mediate the acute phase response seen with inflammation and stress that is often mediated by interleukin-6 (IL-6) and other proinflammatory cytokines. Genes regulated by STAT3 control critical cellular processes such as proliferation, survival, pluripotency, invasion, and angiogenesis. Given the nature of these genes and their effect on cellular behavior, it is not surprising that physiologic STAT signaling is tightly regulated. When a cell is exposed to a cytokine like IL-6, STAT3 becomes phosphorylated and activated for only a matter of minutes. However, shortly after the discovery of physiologic STAT signaling, it was appreciated that in many human cancers abnormal continuous activation of STAT3 and other STATs was occurring. Initially, this was observed in cancers characterized by an activated mutated tyrosine kinase such as Bcr-Abl or epidermal growth factor receptor. However, the prevalence of STAT3 activation in human cancers far exceeds that of known activated kinases. For example, in breast cancer or prostate cancer, more than 70% of primary tumors display constitutive STAT3 activation. In many of these cases, soluble factors such as IL-6 are released from stromal cells or from the tumor cells themselves driving activation of this pathway. Recent evidence from a number of studies, including the elegant analysis by Huang et al in this issue of the Journal of Clinical Oncology, shows how our increased insight into STAT signaling can provide prognostic information for patients with cancer. The authors asked the important question of whether activation of STAT3 has prognostic significance in patients with diffuse large B-cell lymphoma (DLBCL) treated with the standard first-line therapy of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. They performed immunohistochemistry (IHC) using an antibody that specifically recognizes the phosphorylated activated form of STAT3 and quantitated the frequency and intensity of staining in CD20 cells from biopsies. In their cohort, 30% of germinal center B-cell–like and 47% of activated B-cell–like DLBCL samples were positive for STAT3 activation. Their key finding was that the detection of STAT3 phosphorylation was associated with inferior survival in the entire cohort and in the activated B-cell–like subgroup. Although there was a similar trend in the germinal center B-cell–like group, the differences did not reach statistical significance. Although phosphorylation of STAT3 is a marker for activation of this transcription factor, the function of STAT3 is to regulate gene expression in the nucleus. Thus, the authors asked whether it might be possible to define a gene expression pattern reflecting activated STAT3 and whether this would also carry prognostic information. Using a clever genetic strategy, they identified an 11-gene signature of STAT3 activation. They found that this signature also had strong prognostic weight in this patient population. This finding is important for several reasons. First, it supports the notion that STAT3 phosphorylation is not merely a marker of activation of some tangential signaling pathway, but rather that the activation of the transcriptional function of STAT3 is likely the important component. This is reinforced by the JAK JAK Cytokine