The fate of a cell, such as its specific responses to extracellular cues, its commitment to proliferate or which differentiation program to execute, are ultimately the result of specific transcriptional programs. We use the CCAAT/enhancer binding protein (C/EBP) transcription factors as molecular tools in mouse models and in vitro systems to gain insight into the molecular mechanisms that govern specific cellular decisions. The objective of this group is to use C/EBP-deficient mice to characterize basic mechanisms regulating cell growth and differentiation in normal cells within physiologically relevant systems. Next, we want to apply this knowledge to understand the emergence and biology of tumorigenic cells. Our ultimate aim is the identification of molecules and regulatory mechanisms that can be targeted for cancer diagnostics, prognostics or therapy. Specifically, we have used a conditional knockout mouse model to specifically delete C/EBPbeta in mammary elithelial cells. This work revealed that in contrast to previous reports using complete C/EBPbeta null mice, that C/EBPbeta is NOT required for luminal epithelial cell proliferation but rather promotes differentiation. This is relvant, because C/EBPbeta is found over-expressed in breast cancer. The transcription factor C/EBPdelta is a rapid response gene that is transiently induced by cell-type specific stimuli. C/EBPdelta has diverse biological functions depending on the cell type and context. In mammary epithelial cells (MEC), C/EBPdelta inhibits growth or survival. In vitro, C/EBPdelta expression is associated with G0 growth arrest. Several studies documented loss of C/EBPdelta expression in breast tumors with progression of malignancy, and hypermethylation of the C/EBPdelta gene has been described in a subset of human breast tumors. Despite this overwhelming evidence that C/EBPdelta inhibits cell growth of mammary epithelial cells, the molecular mechanism for this activity is unknown. In the mouse mammary gland, C/EBPdelta is transiently induced at the onset of post-lactational involution, in a phase which is characterized by the induction of acute phase response genes and the """"""""battle"""""""" of pro- and antiapoptotic signals that ultimately leads to programed cell death of the epithelial cells. Mice with a null mutation of the C/EBPdelta gene undergo delayed mammary gland involution due to attenuated MEC apoptosis. We have used microarray technology to characterize genes whose expression depend on C/EBPdelta specifically at the onset of apoptosis in the involuting mammary gland. This work revealed that C/EBPdelta regulates important cell cycle regulators. Furthermore, we have identified a potential novel survival signal for MEC and breast tumor cells whose expression in tumors may affect and predict patient response to therapy.
| Smink, Jeske J; Begay, Valerie; Schoenmaker, Ton et al. (2009) Transcription factor C/EBPbeta isoform ratio regulates osteoclastogenesis through MafB. EMBO J 28:1769-81 |
| Sterneck, E; Zhu, S; Ramirez, A et al. (2006) Conditional ablation of C/EBP beta demonstrates its keratinocyte-specific requirement for cell survival and mouse skin tumorigenesis. Oncogene 25:1272-6 |
| Thangaraju, Muthusamy; Rudelius, Martina; Bierie, Brian et al. (2005) C/EBPdelta is a crucial regulator of pro-apoptotic gene expression during mammary gland involution. Development 132:4675-85 |
| Thangaraju, Muthusamy; Sharan, Shikha; Sterneck, Esta (2004) Comparison of mammary gland involution between 129S1 and C57BL/6 inbred mouse strains: differential regulation of Bcl2a1, Trp53, Cebpb, and Cebpd expression. Oncogene 23:2548-53 |
| Huang, A-Mei; Montagna, Cristina; Sharan, Shikha et al. (2004) Loss of CCAAT/enhancer binding protein delta promotes chromosomal instability. Oncogene 23:1549-57 |
