Esta Sterneck, Ph.D.
Dr. Sterneck investigates cell signaling pathways that regulate mammary gland development and tumorigenesis. Work with transgenic mouse models, human cancer cell lines, and tissue analyses revealed that the transcription factor CCAAT/enhancer binding protein delta (CEBPD), can act as a tumor suppressor or promote metastasis. Mechanistic studies showed that CEBPD inhibits migration and invasiveness of tumor cells while also supporting adaptation to hypoxia and pro-inflammatory gene expression. These and ongoing studies contribute to our understanding of how the microenvironment changes cell phenotypes and promotes neoplastic malignancy.
1) breast cancer, 2) mouse models, 3) gene expression, 4) C/EBP, 5) inflammation,
The C/EBPδ Transcription Factor: Dr. Jekyll and Mr. Hyde in Mammary Tumor Biology
My laboratory conducts basic research to better understand cell signaling pathways that regulate mammary gland development and tumorigenesis. In particular, we investigate the physiological functions of the transcription factor CCAAT/enhancer binding protein delta (C/EBPδ), encoded by the CEBPD gene. We use genetically engineered mice and human breast epithelial cell lines to elucidate the molecular mechanisms of CEBPδ's functions in development and tumorigenesis. In addition, we analyze patient samples to guide our approaches and determine the clinical relevance of our observations. Our long-term goal is to understand the normal cell functions and perturbations that affect breast tumor biology.
Gene expression analyses in human tissues show that CEBPD expression is downregulated in breast cancer and is part of a 70-gene expression signature that predicts longer patient survival. These observations and studies in cell lines had suggested that C/EBPδ functions as a tumor suppressor. Our contributions to elucidate the tumor suppressor-like functions of C/EBPδ in mammary epithelial cells include the findings that C/EBPδ augments cyclin D1 protein degradation by the APC/Ccdc27 pathway (Pawar et al., 2010), inhibits the Src tyrosine kinase-induced transformation of breast epithelial cell lines (Sarkar et al., 2012), and augments DNA repair (Huang et al., 2004; Wang et al., 2010). We also obtained the first in vivo evidence of C/EBPδ's tumor-suppressing role, by crossing Cebpd null mice with transgenic MMTV-Neu mice, a model for stochastic mammary tumorigenesis (Balamurugan et al., 2010). Unexpectedly, this approach revealed an additional role of C/EBPδ in promoting metastatic tumor progression. We subsequently discovered that C/EBPδ augments hypoxic and inflammatory signaling events, which are both associated with promoting metastasis, by suppressing expression of FBXW7α (Balamurugan et al., 2010, 2013). FBXW7α is a substrate-binding subunit of the SCF polyubiquitination complex and a bona fide tumor suppressor for several epithelial cancers because it targets a number of oncoproteins for degradation. Our finding that C/EBPδ represses FBXW7α in tumor cells and macrophages suggested alternative roles for C/EBPδ in tumor development, both within mammary epithelial cells and in the tumor microenvironment (Balamurugan et al., 2010, 2013). In addition, we discovered two degradation pathways that downregulate C/EBPδ protein levels: the pro-oncogenic SIAH2 ubiquitin ligase pathway and a pathway requiring the tumor suppressor SCF-FBXW7 ubiquitin ligase (Sarkar et al., 2012; Balamurugan et al., 2013). These findings further corroborate the dual nature of C/EBPδ's functions (see also Balamurugan and Sterneck, 2013).
Our current research is designed to determine the diverse functions of C/EBPδ in tumorigenesis, to elucidate the molecular mechanisms of C/EBPδ signaling and of the switch between its different functions. Specifically, we are identifying target genes of C/EBPδ that mediate its tumor suppressor or tumor promoter function within mammary epithelial cells. Through ChIP-Seq and mRNA-Seq approaches we have identified several new target genes whose expression correlates with better outcome for breast cancer patients, and we are investigating their functions in breast tumor cells. To study tumor promotion by C/EBPδ, we focus on hypoxia and inflammation as mediators of epithelial-mesenchymal transition and cancer cell stemness. We are also investigating the contributions 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. Drs. Goran Landberg (Paterson Institute for Cancer Research, Manchester U.K.), Carlos Caldas (University of Cambridge, UK), David Brown (St. Vincent's Centre for Applied Medical Research, Australia), Fiona Yull (Vanderbilt University), Rosandra Kaplan (NCI), Stephen Hughes (NCI), Sendurai Mani (MD Anderson Cancer Center) and Wendy Woodward (MD Anderson Cancer Center).
Selected Recent Publications
- Oncogene. Epub ahead of print: 2018. [ Journal Article ]
The C/EBPδ protein is stabilized by estrogen receptor α activity, inhibits SNAI2 expression and associates with good prognosis in breast cancer.Oncogene. Dec 1;35(48): 6166-6176, 2016. [ Journal Article ]
- Nat Commun. 4: 1662, 2013. [ Journal Article ]
- Int J Biol Sci. 9: 917-33, 2013. [ Journal Article ]
Identification of a Src tyrosine kinase/SIAH2 E3 ubiquitin ligase pathway that regulates C/EBPδ expression and contributes to transformation of breast tumor cells.Mol. Cell Biol. 32: 320-32, 2012. [ Journal Article ]
Dr. Esta Sterneck received her Ph.D. from the University of Heidelberg following training at the European Molecular Biology Laboratory (EMBL) and the Center for Molecular Biology Heidelberg (ZMBH) in Germany. Her thesis work investigated oncogene cooperation in leukemia cells and revealed their coordinate induction of an essential autocrine growth factor. During her postdoctoral training at the Advanced BioScience Laboratories-Basic Research Program in Frederick, MD, Dr. Sterneck began to study the functions of C/EBP transcription factors, including their roles in normal mammary gland development, through genetically engineered mice. Dr. Sterneck began her independent research with an NCI-Scholar grant before being recruited as a Principal Investigator to the NCI in 2003. Her current research investigates the functions of the C/EBPδ transcription factor as tumor suppressor as well as tumor promoter in breast epithelial cells and cells of the tumor microenvironment.
In 2013, Dr. Sterneck received the NIH Merit Award and the NCI Outstanding Mentor Award.
|Kelli Czarra||Animal Technician (Leidos)|
|Balamurugan Kuppusamy, Ph.D.||Staff Scientist|
|Dipak Poria Ph.D.||Postdoctoral Fellow (Visiting)|
|Shikha Sharan M.S.||Research Biologist|
|Ariana Vitale B.Sc.||Postbaccalaureate Fellow (CRTA)|