Role of Cell-Surface Proteases in Invasion and Metastasis of Breast Cancer
We study a cell surface protease, termed "Fibroblast activation protein-alpha (FAP)" or “seprase”, that is not expressed by normal adult tissues but is expressed in breast cancer. We find that FAP promotes rapid growth and angiogenesis of tumors in a mouse model of human breast cancer.
Our laboratory is now working to identify mechanisms by which FAP converts slow-growing tumors into rapidly tumor growing and invasive tumors. We are investigating the role of the proteolytic activity of FAP in promoting tumor growth by using small molecule inhibitors of FAP as well as by observing the effect of causing expression of mutant FAP that is proteolytically inactive in breast cancer cells. We are also investigating the apparent formation of multifunctional complexes comprising FAP and other molecules on the cell surface. These FAP complexes mediate adhesion, proteolysis, and signal transduction. Research into FAP is likely to yield new information and tools that will be clinically useful for treating breast cancers. Treatment with agents that inhibit the proteolytic activity of FAP might impede growth or prevent metastasis of malignant breast cells. Moreover, when used in conjunction with standard treatment regimes, FAP inhibitors might prevent breast cancer recurrence by containing any malignant cells that survived surgical removal of the tumor and radiation or chemotherapies.
Selected Publications:
Yang, Y., V. MacLeod, M. Bendre, Y. Huang, A. M.Theus, H.-Q. Miao, P. Kussie, S. Yaccoby, J. Epstein, L. J. Suva,
T. Kelly and R. D. Sanderson (2005) Heparanase promotes the spontaneous metastasis of myeloma cells to bone. Blood 105:1303-1309.
Kelly, T. (2005) Fibroblast activation protein-á and dipeptidyl peptidase IV (CD26): cell-surface proteases that activate cell signaling and are potential targets for cancer therapy. Drug Resistance Updates: 8:51-58.
Kelly, T., L. J. Suva, Y. Huang, V. MacLeod, H.-Q. Miao, R. C. Walker, and R. D. Sanderson (2005) Expression of heparanase by primary breast tumors promotes bone resorption in the absence of detectable bone metastases. Cancer Res., 65:5778-84.
Huang, Y., S. Wang, and T. Kelly (2004) Seprase promotes rapid tumor growth and increased microvessel density in a mouse model of human breast cancer. Cancer Res. 64:2712-2716.
Sanderson, R.D., Y. Yang, L.J. Suva, and T. Kelly (2004) Heparan sulfate proteoglycans and heparanase – Partners in osteolytic tumor growth and metastasis. Matrix Biol. 23:341-352.
Goodman, J.D., T.L. Rozypal, and T. Kelly. (2003) Seprase, a membrane-bound protease, alleviates the serum growth requirement of human breast cancer cells. Clin. Exp. Metastasis 20:459-470.
Kelly, T., H.-Q. Miao, Y. Yang, E. Navarro, P. Kussie, Y. Huang, V. MacLeod, J. Casciano, L. Joseph, F. Zhan, M. Zangari, B. Barlogie, J. Shaughnessy, and R.D. Sanderson. (2003) High heparanase activity in multiple myeloma is associated with elevated microvessel density. Cancer Res. 63:8749-8756.
Department of Breast Cancer Research and Development
University of Arkansas for Medical Sciences
4301 W. Markham St, # 824
501-526-5930 (Administrative Office)
501-526-5934 (Fax)
