Characterization and Regulation of C/EBPδ in Human Mammary Epithelial Cell G0 Growth Arrest

CCAAT/Enhancer binding proteins (C/EBPs) are members of the leucine zipper family of transcription factors and play key roles in cell growth, differentiation and apoptosis. C/EBP family member, C/EBPδ, plays an important role in the G0 growth arrest of mouse mammary epithelial cells in vitro and in mouse mammary gland involution in vivo. The role of C/EBPδ in human mammary epithelial cells has not yet been established. Serial Analysis of Gene Expression (SAGE) analysis of human breast tumors, however, has recently demonstrated that C/EBPδ is one of a subset of genes that is down-regulated inbreast cancer. These results suggest that C/EBPδ may play an important role in human mammary epithelial cell growth control. The goal of this dissertation project was three-fold. First, characterize the expression of C/EBPδ and determine its role in G0 growth arrest in normal and tumorigenic human mammary epithelial cells. Secondly, investigate upstream signaling regulators of the C/EBPδ promoter. And lastly, investigate signaling events important for the initiation and maintenance of G0 growth arrest in human mammary epithelial cells. In summary, this dissertation has revealed that activation of the JAK/STAT3 signaling pathway is required for the induction of C/EBPδ and plays a key role in the induction of G0 growth arrest of human mammary epithelial cells. This growth inhibitory signaling pathway is increasingly disrupted in mammary epithelial cells as cells progress from normal to neoplastic. Activation of the STAT3 signaling pathway in normal mammary epithelial cells and the initiation and maintenance of G0 growth arrest is the result of transcriptional up-regulation and secretion of growth inhibitory cytokines (LIF, IL-6, OSM) into the media, establishing an autocrine regulatory mechanism.