A Role for TIMP-1 in Breast Cancer Progression
Annual rept. 1 Jul 2003-30 Jun 2004
LOUISIANA STATE UNIV IN SHREVEPORT HEALTH SCIENCE CENTER
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Breast cancer is the most common life-threatening cancer and second leading cause of cancer deaths in Western women. Death usually results from the complications caused by secondary tumors that result from termed invasion and metastasis, processes that depend on the secretion of proteinases. The level of one such proteinase inhibitor, named TIMP-1, predicted to inhibit invasion, paradoxically has been found to be higher in breast cancers of patients that more often relapse and die as compared to patients that survive. This suggests that this protein may have multiple functions that include both inhibition of cancer promoting proteinases and stimulation of cell-signaling pathways that promote cancer progression. In support of this hypothesis, we have determined that overexpression of TIMP-1 activates Ras, the MAPK pathway and induces epithelial-mesenchymal transition EMT, a process important in invasion of tumor cells into surrounding tissues. Furthermore, TIMP-1 expressing cells were more motile and overexpressed a protein named PAI-1 that has been implicated in breast cancer progression. These studies support clinical studies demonstrating that high tissue levels of TIMP-1 correlate with a bad prognosis and suggest that the reason for this may be because TIMP-1 activates signaling pathways that promote EMT. Future studies will examine this hypothesis.
- Anatomy and Physiology
- Medicine and Medical Research