Role of STAT5b in Breast Cancer Progression and Metastasis

摘要

Signal transducer and activator of transcription 5b (STAT5b) is a transcription factor which promotes growth and survival of a number of cancers, including breast cancer. The objective of this work was to elucidate the role of STAT5b in breast cancer cell migration. Through siRNA knockdown technology, the necessity of STAT5b for migration of two highly aggressive, highly migratory, breast cancer cell lines (BT-549 and MDA-MB-231), was explored. Knockdown of STAT5b inhibited migration of both cell lines by 60-80%. More specifically, STAT5b knockdown suppressed migration of these cells to the extracellular matrix component fibronectin, suggesting that STAT5b is an important signaling component in beta1 integrin-mediated migration of breast cancer cells. Inhibition of migration upon STAT5b knockdown was rescued by wild- type STAT5b as well as transcriptionally inactive Y699F- and dominant-negative forms of STAT5b. In contrast, an SH2 domain defective R618K-STAT5b did not rescue migration. These data indicate that STAT5b-mediated transcription is not required for promoting migration, but SH2 domain interactions are necessary. Upon spreading, STAT5b knockdown cells adopted a striking phenotype characterized by the formation of multiple, highly contractile protrusions. In accordance with these findings, knockdown cells exhibited high levels of myosin light chain phosphorylation, independent of attachment. Additionally, knockdown of STAT5b correlated with loss of polarity, resulting in lack of directionality during wound closure. In summary, the data presented here identifies a novel, SH2- dependent function of STAT5b in regulating beta1 integrin-mediated migration of highly aggressive.