Presently, effective therapies for breast cancer is compromised when cancer cells metastasize to other sites. One extracellular matrix protein, thrombospondin-1 (TSP1) has been shown to inhibit breast cancer metastasis in nude mice. At this time, it is not well understood how TSP1 prevents metastasis. In endothelial cells, TSP1 activates transforming growth factor beta (TGF-beta). TSP1 through TGF-beta could affect the levels and activation of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs), enzymes that modulate the cells' ability to degrade extracellular matrices. The goal of this project is to characterize the relationship between TSP1, TGF-beta, MMPs and TIMPs in breast carcinoma cells to determine whether this pathway could be responsible for TSP1 inhibition of metastasis in vivo. The following questions will be addressed: 1. Does TSP1 activate TGF-beta in breast carcinoma cells? 2. Does TGF-beta affect the activation levels of MMP-2 and 9 and expression levels of TIMP-1 and 2 in breast carcinoma cells? 3. Does the levels of TSP1, TGF-beta, MMPs and TIMPs affect the ability of breast carcinoma cells to invade an extracellular matrix in vitro?
| Yee, Karen O; Streit, Michael; Hawighorst, Thomas et al. (2004) Expression of the type-1 repeats of thrombospondin-1 inhibits tumor growth through activation of transforming growth factor-beta. Am J Pathol 165:541-52 |
