| The Janus Kinase/Signal transducer and activator of transcription (JAK/STAT) pathway relays extracellular signals into cellular responses most commonly through transcriptional activation by STATs. The JAK2/STAT5 pathway is particularly important for functional mammary gland development by promoting cellular proliferation, differentiation, and survival; however, little is known about the specific target genes and mechanisms by which it promotes cell survival and neoplastic transformation. This pathway also plays a critical role in hematopoiesis and is found aberrantly activated in myeloproliferative diseases. It is unclear, however, whether hematological disease induced by active STAT5 remains dependent upon it.;By utilizing genetically engineered mouse models, we first demonstrated that active STAT5 delays involution in an AKT1-dependent manner. Subsequent studies revealed that active STAT5 transcriptionally regulates the PI3-kinase regulatory and catalytic subunits, p85α and p110α, in mammary epithelial cells in vivo and in vitro. In addition, active STAT5 also associates with the p85α subunit of the PI3-kinase during lactation, which is a mechanism believed to further increase the catalytic activity of p110α, thereby promoting a dual means of P13-kinase regulation. Furthermore, overexpression of active STAT5 was capable of increasing tumor penetrance by more than 50% in Pten G129E females predisposed to mammary cancer through an uninhibited PI3-kinase. Transplantation experiments further demonstrated that downregulation of active STAT5 slowed tumor growth in vivo. Next, we conditionally deleted Stat5 from the mammary epithelium of Pten G129E females and this completely blocked alveolar genesis, proliferative expansion, and hyperplasia consistently observed in PtenG129E mammary glands. Finally, to address the role of STAT5 in hematological disease, we conditionally overexpressed active STAT5 within the myeloid lineage. This induced a lethal phenotype characterized by excessive granulopoiesis and extravasation into the lungs. Interestingly, the downregulation of active STAT5 within sick mice was sufficient to completely clear the lungs, restore granulocyte counts to normal, and return the animals to full health. Collectively, these studies provide novel insights into the multifaceted roles that the JAK2-STAT5 pathway plays in developmental processes and disease. |
