Balamurugan Kuppusamy, Ph.D.
Dr. Kuppusamy investigates cell signaling pathways involved in breast and glioblastoma tumorigenesis. His recent work discovered that the transcription factor CCAAT/enhancer binding protein delta (CEBPD) can act as a tumor suppressor and in addition also promote metastasis. Mechanistic studies in both mouse and human cells revealed that CEBPD supports adaptation to hypoxia and pro-inflammatory gene expression through suppression of another tumor suppressor called FBXW7. FBXW7 is part of the SCF E3 ubiquitin ligase complex that targets many pro-oncogenic substrates for degradation and was found to also downregulate CEBPD protein. The mutual repression of these two factors may serve to fine-tune the cellular adaptation to hypoxia and inflammatory signaling. BY unraveling the complex signaling pathways involved in metastatic progression of breast cancers, with specific focus on inflammatory and hypoxic tumor microenvironmental conditions, may lead toward the identification of new therapeutic targets.
1) hypoxia signal transduction, 2) cancer stem cells, 3) mouse models, 4) breast cancer, 5) CEBPD transcription factor, 6) FBXW7 inflammation
Our lab investigates the role of CCAAT/enhancer binding protein delta (CEBPD) transcription factor in mammary gland development and breast tumorigenesis. CEBPD is emerging as an important modulator of cell signaling, whose roles are cell type and context-dependent (Balamurugan and Sterneck, 2013). We have identified a dual role for CEBPD, in breast cancer. A brief summary of recent publications is provided below.
“The tumor suppressor CEBPD inhibits FBXW7 expression and promotes mammary tumor metastasis (Balamurugan et al., EMBO J, 2010)”. This study documented the first in vivo evidence for a tumor suppressor function of CEBPD. At the same time, we discovered unexpectedly that CEBPD promotes mammary tumor metastasis. The study revealed that CEBPD is expression is induced by hypoxia and in turn inhibits the expression of the tumor suppressor “F-box and WD-repeat domain containing protein 7alpha” (FBXW7alpha). This elucidated how CEBPD augments the mTOR/AKT/S6K/HIF-1 pathway and demonstrated a novel role and molecular mechanism for C/EBPd in promoting cell survival and adaptation to hypoxia.
“FBXW7alpha attenuates inflammatory signaling by downregulating CEBPD and its target gene Tlr4 (Balamurugan et al., Nature Communications, 2013)”. This study identified a previously unknown role for the CEBPD target gene FBXW7alpha as an attenuator of inflammatory signaling. We discovered that CEBPD in turn is targeted for degradation by FBXW7alpha and that the pro-inflammatory TLR4 receptor is a direct target gene of CEBPD, which is critical for macrophage activation. Furthermore, we show that CEBPD modulates the inflammatory signature in mammary tumors. This study provides novel insights into the regulation of the inflammatory signaling and opens new directions for the study of tumor regulating functions of CEBPD in the tumor microenvironment. Altogether, our published work demonstrates that CEBPD augments whereas FBXW7 prevents hypoxia and inflammatory signaling pathways, which are involved in tumor progression.
Our current research focuses on the role of CEBPD as a “signaling hub” that integrates and amplifies stemness promoting pathways in breast cancer and glioblastoma cells. Furthermore, we aim to develop tools to specifically target CEBPD and thereby eradicate metastatic cancer cells.
- International J. Cancer. 138(5): 1058-1066, 2016.
- Nature Commun.. 4: 1662, 2013.
- International J. Biol. Sci.. 9: 917-933, 2013.
The tumor suppressor CCAAT/Enhancer Binding Protein delta inhibits FBXW7 expression and promotes mammary tumor metastasis.EMBO J.. 29: 4106-4117, 2010.
C/EBPδ targets cyclin D1 for proteasome-mediated degradation via induction of Cdc27/Apc3 expression.Proc Natl Acad Sci U S A. 107: 9210-9215, 2010.
Dr. Balamurugan Kuppusamy obtained his PhD from the University of Madras, Chennai, India. Dr. Kuppusamy pursued his postdoctoral studies at the University of Zurich, Switzerland and at the National Cancer Institute. Since March 2015, he serves as a staff scientist in the Laboratory of Cell and Developmental Signaling (NCI/CCR). Dr. Kuppusamy is a recipient of NCI Cancer Genetics and Signaling Fellowship. In 2011 and 2012, Dr. Kuppusamy received the NIH “Fellows Award for Research Excellence” and NCI Fellows and Young Investigators "Outstanding Achievement in Science Award", respectively. In 2015, Dr. Kuppusamy was awarded a research grant from the METAvivor Foundation to study the role of the CEBPD-FBXW7 signaling pathway in inflammatory breast cancer.