Deregulation of c-Myc expression is implicated in pathogenesis of many human cancers including breast cancer. Estrogen receptor alpha can increase the rate of c-Myc transcription through the recruitment of a variety of cofactors to the c-Myc promoter, yet the precise roles of these cofactors in transcription and tumorigenesis are largely unknown. We have identified a putative tumor suppressor, TIP30, also called CC3, that can specifically regulate ER alpha-mediated c-Myc transcription. Our objective is to investigate the role of TIP30 in the regulation of transcription of ER alpha-target genes and tumorigenesis.
The specific aims of this proposal are to: 1) investigate whether deletion of TIP30 increases expression of ER alpha-target genes in the epithelial cells of the mammary glands in vivo. 2) investigate whether breast cancers from patients harbor mutations in the TIP30 gene. 3) evaluate the susceptibility of TIP30-mutant mice to mammary tumorigenesis. These studies will have a significant impact on three important aspects. They will provide: 1) a molecular basis for a TIP30-mediated regulatory pathway in mammary gland development, 2) direct evidence for the role of a transcription cofactor in breast carcinogenesis, and 3) a system for studying biologically relevant factors and events responsible for the pathogenesis of breast cancers. Therefore, this proposal will not only yield insights into the mechanisms for regulation of gene expression intumorigenesis but also provide a potential target for the diagnosis and treatment of human cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK066110-01
Application #
6710499
Study Section
Pathology B Study Section (PTHB)
Program Officer
Margolis, Ronald N
Project Start
2004-02-01
Project End
2009-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
1
Fiscal Year
2004
Total Cost
$257,250
Indirect Cost
Name
University of Nebraska Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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Li, A; Zhang, C; Gao, S et al. (2013) TIP30 loss enhances cytoplasmic and nuclear EGFR signaling and promotes lung adenocarcinogenesis in mice. Oncogene 32:2273-81, 2281e.1-12
Zhang, Chengliang; Li, Aimin; Zhang, Xinchun et al. (2011) A novel TIP30 protein complex regulates EGF receptor signaling and endocytic degradation. J Biol Chem 286:9373-81
Zheng, Fei; Zhou, Xianju; Luo, Yongneng et al. (2011) Regulation of brain-derived neurotrophic factor exon IV transcription through calcium responsive elements in cortical neurons. PLoS One 6:e28441
Zhang, Chengliang; Li, Aimin; Gao, Shenglan et al. (2011) The TIP30 protein complex, arachidonic acid and coenzyme A are required for vesicle membrane fusion. PLoS One 6:e21233
Zhou, Xianju; Xiao, Hua; Wang, Hongbing (2011) Developmental changes of TrkB signaling in response to exogenous brain-derived neurotrophic factor in primary cortical neurons. J Neurochem 119:1205-16
Zhang, Chengliang; Mori, Mikito; Gao, Shenglan et al. (2010) Tip30 deletion in MMTV-Neu mice leads to enhanced EGFR signaling and development of estrogen receptor-positive and progesterone receptor-negative mammary tumors. Cancer Res 70:10224-33
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