Tid1 is the human counterpart of the Drosophila tumor suppressor Tid56. Tid56 null mutation causes tumorous imaginal discs resulting from continuous cell proliferation without differentiation. To date, the mechanism of tumor suppression of Tid56 in Drosophila, as well as the cellular function of Tid1 in human tumorigenesis, are poorly understood. By yeast two-hybrid screening, we found that Tid1 interacts with the signaling domain of ErbB2/Her2. Subsequent studies demonstrated that increased expression of Tid1 protein in ErbB2-overexpressing breast cancer cells facilitated the ErbB2 ubiquitination/degradation, as well as caused growth inhibition of these cells. Moreover, by depleting the physiological levels of Tid1 in breast cancer cells using the technique of RNA interference (RNAi), we discovered that the metastatic potential of Tid1-depleted cells was substantially enhanced, resulting from the increased production of interleukin-8 (IL-8) through upregulation of NF-kB activity in the Tid1-knockdown cells. Thus, since Tid1 attenuates signals generated from the ErbB2 receptor as well as negatively regulates the activity of NF-kB, we hypothesize that Tid1, like its Drosophila counterpart, may be an important tumor suppressor, especially in breast carcinogenesis and metastasis. To evaluate this hypothesis in an animal model, we have established a conditional knockout (CKO) animal in which the Tid1 gene can be deleted specifically in mammary epithelial cells. Herein we propose to investigate and evaluate the mechanistic role of Tid1 as a tumor suppressor in regulating tumorigenesis and metastasis of breast cancer not only at the molecular and cellular levels but also in an organismal context.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA114059-05
Application #
7842545
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Ault, Grace S
Project Start
2006-07-17
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
5
Fiscal Year
2010
Total Cost
$326,609
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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