In this revised application, the investigators have designed experiments to investigate the biological effects of two functions of tTG. First, Balb-c 3T3 fibroblasts and human breast cancer cells will be transfected with tTG and tTG mutants and the role of tTG overexpression on cell proliferation will be investigated by flow cytometry. Second, the effect of tTG overexpression from stromal fibroblasts on the growth and metastasis of human breast cancer cells will be investigated. Finally, the role of tTG in the epithelium will be determined by the overexpression of tTG in transgenic mice. Targeting the expression of tTG to the mammary epithelium using the MMTV promoter will make it possible to examine the influence of tTG on the normal process of mammary gland development, lactation and the subsequent involuton of the gland post-lactation. Finally, to determine the influence of tTG on breast cancer cell growth and development in an in vivo model of human breast cancer, MMTV/tTG transgenic mice will be mated with transgenic mice that express the activated neu-oncogene and the rate of tumor growth and development will be assessed. Knowledge concerning the physiology and the pathophysiology of tTG in normal and malignant mammary epithelial cells may lead to novel strategies in the treatment of breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA071753-03
Application #
2895638
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Mohla, Suresh
Project Start
1997-08-01
Project End
2002-05-31
Budget Start
1999-07-14
Budget End
2000-05-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Lai, T-S; Tucker, T; Burke, J R et al. (2004) Effect of tissue transglutaminase on the solubility of proteins containing expanded polyglutamine repeats. J Neurochem 88:1253-60
Ariens, Robert A S; Lai, Thung-Shenq; Weisel, John W et al. (2002) Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms. Blood 100:743-54
Blackwell, K; Haroon, Z; Broadwater, G et al. (2000) Plasma D-dimer levels in operable breast cancer patients correlate with clinical stage and axillary lymph node status. J Clin Oncol 18:600-8
Lai, T S; Slaughter, T F; Peoples, K A et al. (1999) Site-directed mutagenesis of the calcium-binding site of blood coagulation factor XIIIa. J Biol Chem 274:24953-8