My laboratory conducts basic research investigating the molecular mechanisms that regulate cell growth and survival, specifically in mammary epithelial and breast tumor cells. We use mouse models and cells derived from these animals to characterize the molecular signaling pathways in tumor cells and in normal mammary epithelial cells within the mammary gland life cycle. We also study signaling pathways in human breast tumor cells in vitro, and we analyze patient samples to determine the clinical relevance of our observations. Specifically, we use the C/EBPdelta transcription factor as a molecular tool. Gene expression analyses in human tumors and genetic studies in cell lines in vitro strongly suggest that C/EBPdelta is a tumor suppressor gene. Our previous contributions to this model were the findings that C/EBPdelta augments genomic stability in mouse embryo fibroblasts in culture (Huang et al., 2004), and that C/EBPdelta promotes cell death of mouse mammary epithelial cells during postlactational involution (Thangaraju et al., 2005). Our subsequent investigations have been focused on characterizing the specific molecular mechanisms by which C/EBPdelta exerts tumor suppressor activity. We have discovered that C/EBPdelta induces the expression of the Cdc27/APC3 subunit of the anaphase promoting complex/cyclosome (APC/C), which in turn results in degradation of the pro-oncogenic cell cycle regulator cyclin D1. Like C/EBPdelta, and in contrast to cyclin D1, we find that Cdc27 is downregulated in several breast cancer cell lines, suggesting that Cdc27 itself may be a tumor suppressor (Pawar et al., 2010, Proc. Natl. Acad. Sci. USA 107(20):9210-5. Analysis of proteins interacting with C/EBPdelta led to the discovery that C/EBPdelta interacts with Fanconi anemia D2 (FANCD2), a protein involved in replication associated DNA repair. C/EBPdelta augments DNA repair by facilitating the interaction of FANCD2 with importin 4 and, as a result, the nuclear import of FANCD2. This study identified a novel non-transcriptional activity of C/EBPdelta, and revealed a new molecular mechanism for its tumor suppressor function (Wang et al., 2010, Proc. Natl. Acad. Sci. USA, 107(37):16131-6). We used transgenic mice overexpressing the Neu/HER2/ERBB2 proto-oncogene in the mammary gland to confirm for the first time in an animal model that C/EBPdelta can function as a tumor suppressor. Surprisingly, this study also revealed that C/EBPdelta is necessary for efficient tumor metastasis. We found that C/EBPdelta expression is induced by hypoxia and that C/EBPdelta inhibits expression of the tumor suppressor FBXW7, thereby augmenting the mTOR/AKT/S6K/HIF-1 pathway. These findings define a role for C/EBPdelta in metastasis promotion despite its primary tumor suppressor activity. Hence, C/EBPdelta is a new example for the TGF-beta paradox of cancer progression, acting as a tumor suppressor at early stages and promoting metastasis at later stages (Balamurugan et al., 2010, EMBO J.29(24):4106-17). Tumor metastasis is the most serious challenge for managing cancer as a chronic disease. A better understanding of the basic biology of metastatic progression and the requirements of metastatic cells for growth and survival is pivotal for future therapeutic advances. We have identified pro- and anti-metastatic activities of C/EBPdelta. Therefore, the focus of the groups current investigations is on promoting our understanding of these seemingly contradictory activities: (a) to decipher the functions of C/EBPdelta at different stages of metastatic progression, (b) to investigate the role of C/EBPdelta in mesenchymal to epithelial transition, (c) to characterize the role of C/EBPdelta in the cellular response to chemotherapeutics, (d) to identify the target genes and molecules mediating these effects of C/EBPdelta, and (e) we continue to use C/EBPdelta-deficient mice to investigate signaling pathways that regulate mammary development and tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010307-12
Application #
8348969
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2011
Total Cost
$932,892
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Mendoza-Villanueva, D; Balamurugan, K; Ali, H R et al. (2016) The C/EBP? protein is stabilized by estrogen receptor ? activity, inhibits SNAI2 expression and associates with good prognosis in breast cancer. Oncogene 35:6166-6176
Pawar, Snehalata A; Shao, Lijian; Chang, Jianhui et al. (2014) C/EBP? deficiency sensitizes mice to ionizing radiation-induced hematopoietic and intestinal injury. PLoS One 9:e94967
Veltmaat, Jacqueline M; Ramsdell, Ann F; Sterneck, Esta (2013) Positional variations in mammary gland development and cancer. J Mammary Gland Biol Neoplasia 18:179-88
Balamurugan, Kuppusamy; Sterneck, Esta (2013) The many faces of C/EBP? and their relevance for inflammation and cancer. Int J Biol Sci 9:917-33
Balamurugan, Kuppusamy; Sharan, Shikha; Klarmann, Kimberly D et al. (2013) FBXW7? attenuates inflammatory signalling by downregulating C/EBP? and its target gene Tlr4. Nat Commun 4:1662
Ko, Chiung-Yuan; Chang, Ling-Hua; Lee, Yi-Chao et al. (2012) CCAAT/enhancer binding protein delta (CEBPD) elevating PTX3 expression inhibits macrophage-mediated phagocytosis of dying neuron cells. Neurobiol Aging 33:422.e11-25
Sarkar, Tapasree Roy; Sharan, Shikha; Wang, Jun et al. (2012) Identification of a Src tyrosine kinase/SIAH2 E3 ubiquitin ligase pathway that regulates C/EBP? expression and contributes to transformation of breast tumor cells. Mol Cell Biol 32:320-32
Balamurugan, Kuppusamy; Wang, Ju-Ming; Tsai, Hsin-Hwa et al. (2010) The tumour suppressor C/EBP? inhibits FBXW7 expression and promotes mammary tumour metastasis. EMBO J 29:4106-17
Pan, Yen-Chun; Li, Chien-Feng; Ko, Chiung-Yuan et al. (2010) CEBPD reverses RB/E2F1-mediated gene repression and participates in HMDB-induced apoptosis of cancer cells. Clin Cancer Res 16:5770-80
Hour, Tzyh-Chyuan; Lai, Yan-Liang; Kuan, Ching-I et al. (2010) Transcriptional up-regulation of SOD1 by CEBPD: a potential target for cisplatin resistant human urothelial carcinoma cells. Biochem Pharmacol 80:325-34

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