Signal transducer and activator of transcription 5a/b: biomarker and therapeutic target in prostate and breast cancer

Abstract

The search for new therapeutic strategies for prostate and breast cancer is of significant interest. Signal transducer and activator of transcription 5a/b (Stat5a/b) controls viability and growth of prostate cancer. Nuclear active Stat5a/b expression is clustered to high grade prostate cancers, predicts early disease recurrence and promotes metastatic dissemination of prostate cancer. In breast cancer, the role of Stat5a/b is more complex. In rodent model systems, Stat5a/b may promote malignant transformation and enhance growth of the breast tumors. In contrast, Stat5a/b activation in established human breast cancer positively correlates with tumor differentiation, prevents metastatic dissemination, and predicts favorable clinical outcome of node-negative breast cancer. Here we review the molecular structure and biological functions of Stat5a/b and discuss the potential applications of Stat5a/b for therapy development and as a prognostic marker for prostate and breast cancer.

Fig. 1. Schematic structure of Stat5a and Stat5b with domains and specific amino acids mediating important functions

N-terminal domain (oligomerization domain) is responsible tetramerization. Coiled Coil domain is essential for interaction with chaperones and recruitment of co-activators and co-repressors. DNA-binding domain recognizes and binds to GAS element on DNA. Linker domain mediates stabilization of the DNA binding. SH2 domain is essential for the recruitment of Stat5a/b to the receptor and for Stat5a/b dimerization. Transactivation domain is responsible for interaction with co-activators and transcriptional activity. Glycosylation of threonine 92 (T92) is crucial for interaction with p300/CREB-binding protein. Phosphorylation of tyrosine 694/699 (Y694/699) is essential for Stat5a/b activation. Phosphorylation of serines 710/715, 725/730, 779 may inhibit transcriptional activity and signal duration.

Figure 2. The canonical Jak2-Stat5a/b pathway and its functional interaction with androgen receptor signaling in prostate cancer cells

The Jak2-Stat5 signaling cascade involves stimulation of the prolactin receptor (PrlR) followed by transphosphorylation and activation of receptor – associated kinase Jak2. Stat5a/b is recruited to the active receptor through its SH2 domain. Following Jak2-mediated Stat5a/b phosphorylation, active Stat5a/b forms a dimer and translocates to the nucleus. The Stat5a/b dimer recognizes and binds GAS elements (TTC(C/T)N(G/A)GAA) on the DNA, initiating transcription of target genes. In human prostate cancer cells, active Stat5a/b transcriptionally synergizes, physically interacts, and enhances nuclear localization of active androgen receptor (AR).