Tyrosine kinases are regulatory proteins that play a central role in cell growth and differentiation. In preliminary work, the expression of tyrosine kinases in breast cancer cell lines was compared to normal-like breast cells using a tyrosine kinase differential display assay. The nuclear tyrosine kinase Rak was downregulated or not expressed in several breast cancer cell lines. Furthermore, the adenovirus early gene E1A, which is known to inhibit the growth of breast cancer cell lines, upregulated Rak expression. Enhanced expression of Rak in breast cancer cells had a growth suppressing activity as measured by a decrease in colony formation efficiency. Surprisingly, little is known about the role of Rak in cells and its mechanism of action. This proposal will test the hypothesis that Rak inhibits tumor cell growth, and that loss of expression of Rak plays a role in breast cancer. First, the effect of Rak expression on tumor cell growth will be assessed in vitro by cell counts, the colony formation assay and the soft agar assay, and tested in vivo. Second, the effect of Rak on the sensitivity of breast cancer cells to apoptosis and on the cell cycle will be studied. The contribution of critical domains of Rak to its function will be studied by deletion and mutation analysis. Third, expression of Rak in breast cancers of various grades and metastatic potentials will be determined by immunohistochemical analysis. These studies will delineate the role of Rak in cell growth and its mechanism of action. From a scientific standpoint, determining Rak's mechanism of action will significantly enhance our understanding of how cell growth is regulated. From a clinical standpoint, Rak may be a useful prognostic marker, and a gene therapy agent. Furthermore, identifying Rak's role in tumor growth will allow us to better tailor the specificity of tyrosine kinase inhibitors used in clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA091834-02
Application #
6522694
Study Section
Subcommittee G - Education (NCI)
Program Officer
Eckstein, David J
Project Start
2001-08-03
Project End
2006-07-31
Budget Start
2002-08-01
Budget End
2003-01-31
Support Year
2
Fiscal Year
2002
Total Cost
$68,040
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030