Targeting of Breast Cancer through MT1-MMP/Tetraspanin Complexes
Final rept. 1 Aug 2008-31 Jul 2011
DANA-FARBER CANCER INST BOSTON MA
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The proteolytic enzyme MT1-MMP, which is frequently upregulated on the surface of breast cancer cells compared to normal breast cells, makes a major contribution towards breast cancer growth, invasion and metastasis. Another protease, called ADAM10, also contributes to breast cancer. The purpose of our studies was to investigate how tetraspanin proteins regulate the maturation and functions of proteases MT1-MMP and ADAM10. We hypothesized that manipulationalteration of tetraspanin proteins e.g. CD9, CD81, TSPAN12 could diminish the functions of associated cell surface proteases e.g. MT1-MMP, ADAM10, thereby limiting breast cancer cell functions. Results obtained strongly support this hypothesis, as we found that alteration of tetraspanin complexes had a major effect on the functions of cell surface proteases. More specifically, we demonstrated three different strategies for disrupting tetraspanin functions i RNAi ablation, ii Dominant negative mutation, and iii C-terminal tail disruption. Also, we determined that EWI-2 action as a tumor suppressor may involve displacement of MT1-MMP from tetraspanin complexes. This could possibly be exploited using synthetic mimics of EWI-2 as anti-tumor agents. In conclusion, our results suggest that perturbation of tetraspanin proteins may provide an unconventional approach towards limiting the growth, invasion and metastasis of breast cancer cells.
- Anatomy and Physiology
- Medicine and Medical Research