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Abstract:
Metastatic breast cancer cells express high levels of the transforming growth factor beta(TGF-beta). Although TGF-beta is a potent tumor suppressor, it can promote formation of metastases by stimulating an epithelial to mesenchymal transition (EMT), cell migration, and changes in tumor microenvironment. Our initial observation indicated that p38 mitogen activated protein kinase (p38 MAPK) is required for these TGF-beta responses in epithelial cells. Thus, p38 MAPK is a potential target for selective therapeutic intervention. The purpose of this research is (1) to examine the role of p38 MAPK in tumor cell motility and invasiveness, and (2) to evaluate the efficacy of p38 MAPK inhibitors. Here, we report that expression of constitutively active TGF-beta type I receptor Alk5-204D in breast cancer MDA-MB-231 cells results in a 4-fold increase in pulmonary macrometastatic lesions. Alk5-204D stimulated cell motility and a nearly 5-fold increase in matrigel invasion. Zymography analysis revealed a significant increase in matrix metalloproteinase 9 (MMP9, gelatinase B) activity but not in MMP2 (gelatinase A). Tumor cell invasion was suppressed by p38 MAPK inhibitors and MMP inhibitor GM6001. Thus, the TGF-beta- p38Mapk signaling cascade may contribute to metastasis by increasing cell motility and MMP9 activity, and p38 MAPK inhibitors block these responses.
| Limitations: |
 APPROVED FOR PUBLIC RELEASE DOCUMENT PARTIALLY ILLEGIBLE |
| Description: |
Annual rept. 15 May 2003-14 May 2004 |
| Pages: |
41 |
| Report Date: |
JUN 2004 |
| Contract Number: |
DAMD17-02-1-0602 |
| Report Number: |
A901724 |
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