Expression of tumor-promoting factors such as cytokines and lipid molecules from tumor cells play critical roles in tumor growth and metastasis. However, the mechanisms by which tumor cells produce these factors are still largely unknown. Recently, we have found that the expression of tristetraprolin (TTP), a zinc finger protein promoting mRNA decay of many target genes, is markedly reduced in breast tumors and tumor cells. More importantly, TTP deficient mice show increased metastases and reduced survival in a mouse mammary gland tumor model. Therefore, we hypothesize that the impaired TTP expression in breast tumor cells promotes tumor metastases via enhancing expression of tumor-promoting factors. TTP may serve as a novel therapeutic target for breast cancer treatment. TTP is a member of CCCH tandem zinc finger proteins and involved in the regulation of inflammatory responses at the post-transcriptional level. TTP binds to adenine-uridine-rich elements (AREs) within the 3'untranslated region (3'UTR) causing destabilization of mRNAs encoding TNF-1, GM-CSF, et al. Overproduction of the proinflammatory cytokines in TTP knockout mice results in a severe systemic inflammatory response including arthritis, autoimmunity and myeloid hyperplasia. Collectively, all evidence indicates that TTP is a critical protein involved in the control of inflammation and maintenance of homeostasis. We recently found that the reduced TTP expression in breast tumors was correlated with increased Th17 cells and enhanced IL-23 expression in the tumor microenvironment. IL-23 has been shown to play an important role in tumor progression by promoting tumor growth and metastasis. Our data indicate for the first time that breast tumor cells could behave like macrophage and DCs to secrete IL-23. In addition, over- expression of TTP in breast tumor cells suppressed IL-23 expression. Since the molecular mechanisms of the enhanced IL-23 and reduced TTP expression in breast tumor cells are largely unknown, in this study, we propose to: (1) Investigate the molecular mechanisms and signaling pathways by which TTP inhibits IL-23 expression in breast tumor cells;(2) Identify the molecular mechanisms that regulate TTP expression in breast tumor cells;(3) Evaluate the therapeutic effects of targeting IL-23 and TTP expression in tumor cells on breast tumor growth and metastasis. Our long-term goal is to elucidate the cellular, molecular and immunologic mechanisms by which TTP suppresses breast tumor progression, and ultimately to develop therapeutic approaches that could reconstitute TTP expression in breast tumors in a tumor-specific manner as a novel breast cancer treatment.

Public Health Relevance

Expression of tumor-promoting factors by tumor cells play critical roles for tumor growth and metastasis. We hypothesize that the impaired tristetraprolin (TTP) expression in breast tumor cells promotes tumor metastasis via enhancing expression of tumor-promoting factors. Our goal is to elucidate the cellular, molecular and immunologic mechanisms by which TTP suppresses breast tumor progression, and ultimately to develop therapeutic approaches that could reconstitute TTP expression in breast tumors in a tumor-specific manner as a novel breast cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA163808-01
Application #
8221172
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Snyderwine, Elizabeth G
Project Start
2012-09-08
Project End
2017-06-30
Budget Start
2012-09-08
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$311,250
Indirect Cost
$103,750
Name
Saint Louis University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Huang, Shengping; Miao, Ruidong; Zhou, Zhou et al. (2013) MCPIP1 negatively regulates toll-like receptor 4 signaling and protects mice from LPS-induced septic shock. Cell Signal 25:1228-34
Gu, Ling; Ning, Huan; Qian, Xuesong et al. (2013) Suppression of IL-12 production by tristetraprolin through blocking NF-kcyB nuclear translocation. J Immunol 191:3922-30
Qian, Xuesong; Gu, Ling; Ning, Huan et al. (2013) Increased Th17 cells in the tumor microenvironment is mediated by IL-23 via tumor-secreted prostaglandin E2. J Immunol 190:5894-902