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Esta Sterneck, Ph.D.
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Biography
Dr. Esta Sterneck received her Ph.D. in 1992 from the University of Heidelberg following training at the European Molecular Biology Laboratory and the ZMBH Center for Molecular Biology, Heidelberg, Germany. She was then recruited as a postdoctoral fellow to the Advanced BioScience Laboratories-Basic Research Program in Frederick, MD. Dr. Sterneck began her independent research with an NCI-Scholar grant before being recruited as a Principal Investigator in 2003.Research
Regulation of mammary gland and breast cancer cells by the C/EBPδ transcription factor
This laboratory conducts basic research investigating the molecular pathways engaged by the transcription factor C/EBPδ, with a particular focus on the mammary gland and breast tumor biology. We use genetically engineered mice and human breast cancer cell lines to elucidate biological and molecular mechanisms of CEBPδ action in development and tumorigenesis, and we analyze patient samples to determine the clinical relevance of our observations. Our long-term goal is to further our understanding of normal cell functions and the perturbations that contribute to breast tumor biology.
Our investigations revealed that C/EBPδ can be both a tumor suppressor as well as a tumor promoter, depending on the cell type, cellular environment, and stage of tumor development. Gene expression analyses in human tumors and genetic studies with cell culture lines have implicated C/EBPδ as a tumor suppressor gene. In support of this notion, we found that C/EBPδ induces the expression of the Cdc27/APC3 subunit of the anaphase promoting complex/cyclosome (APC/C), which in turn results in degradation of the cell cycle regulator cyclin D1 (Pawar et al., 2010, PNAS). Furthermore, we have shown that C/EBPδ can augment genomic stability (Huang et al., 2004, Oncogene) and promote DNA repair by catalyzing the nuclear translocation of FANCD2 (Wang et al., PNAS 2010). In the mouse mammary gland, C/EBPδ promotes cell death of mammary epithelial cells during postlactational involution (Thangaraju et al., 2005, Development). In human breast epithelial cell lines, the C/EBPδ protein is targeted for degradation by the SIAH2 E3 ligase in a manner, which requires Src tyrosine kinase activity. Consistent with a tumor-suppressor function, downregulation of C/EBPδ was found to augment breast epithelial cell transformation by Src, whereas stabilization of C/EBPδ promoted the response of tumor cell lines to Src-kinase inhibitors in vitro. This study provided new insights into the regulation of C/EBPδ expression and the mechanisms by which Src kinase promotes transformed features in breast epithelial cell lines (Sarkar et al., 2012, MCB).
We have evaluated the role of C/EBPδ in vivo with the transgenic MMTV-Neu mouse model of mammary tumorigenesis. C/EBPδ null mice exhibited increased tumor incidence, indicating that C/EBPδ indeed acts as a tumor suppressor in this in vivo system. However, these mice also had reduced distant metastases, demonstrating that C/EBPδ may have additional roles in tumor progression. Our mechanistic analyses revealed that C/EBPδ expression is induced by hypoxia and in turn inhibits the expression of the tumor suppressor FBXW7. Thereby, C/EBPδ augments the mTOR/AKT/S6K/HIF-1 pathway, which is critical for the adaptation to hypoxia, a metastasis-promoting condition. Our findings have defined a novel role for C/EBPδ in this pathway (Balamurugan et al., 2010, EMBO J.). In addition, we found that a role of C/EBPδ in macrophage activation and the innate immune response may underly in part both its role as a tumor suppressor as well as in promoting metastasis (Balamurugan et al., 2013, Nature Commun.).
Building on our previous discoveries, the group's current and future investigations have two main goals: (1) Further characterization of the role and mechanisms of C/EBPδ in signaling pathways within breast epithelial cells and (2) Characterization of cell type specific functions of C/EBPδ that influence mammary tumor development. Specifically, we are investigating the molecular mechanism(s) that determine whether C/EBPδ acts as a tumor suppressor or tumor promoter within mammary epithelial cells, and the contribution of C/EBPδ functions in the tumor microenvironment on mammary tumor development. Towards this goal, we have recently developed mice with a conditional knockout allele of C/EBPδ.
Collectively, these approaches will provide deeper insight into the molecular mechanisms that modulate mammary epithelial cell biology and may allow us to better understand the complexity and diversity of cellular processes in normal development and breast cancer.
Current collaborators include: Drs. Goran Landberg (Paterson Institute for Cancer Research, Manchester U.K.), Carlos Caldas (University of Cambridge, UK), Thierry Roger (University of Lausanne, Switzerland), Ju-Ming Wang (National Cheng Kung University,Taiwan), David Brown (St. Vincent's Centre for Applied Medical Research, Australia), Fiona Yull (Vanderbilt University), Sendurai Mani (University of Texas MD Anderson Cancer Center), Jonathan Keller (NCI), Rosandra Kaplan (NCI)
This page was last updated on 4/30/2013.
