Epithelial-mesenchymal Transition and Genomic Instability in Breast Cancer

Matrix metalloproteinases (MMPs) are essential for many physiological processes, but inappropriate expression of MMPs can facilitate the development and progression of tumors. Recognition of the relationship between MMPs and malignancy led to clinical trials of broad-spectrum MMP inhibitors as cancer therapeutics, but the results were disappointing. The failure of the clinical trials was due in large part to the propensity of the MMP inhibitors to inhibit essential physiological processes. Therapeutic strategies that target tumor-specific MMP-dependent effects may prove more promising.

Previous studies and our preliminary data show that exposure of mammary epithelial cells to selected MMPs causes cleavage of a cell surface molecule that stimulates cellular production of reactive oxygen species (ROS). MMP-dependent production of ROS causes cells to undergo epithelial-mesenchymal transition (EMT), a fundamental phenotypic alteration associated with progression to metastasis, and compromises the cellular genomic stability. We seek to identify the specific steps associated with the MMP-induced malignant transformation so as to determine potential points for therapeutic intervention.

Currently, we are working to identify the proteolytic target of MMPs that stimulates the development of ROS. We are defining the specific factors responsible for the increased expression of Snail and Twist and dissecting the relative role of these transcription factors in MMP-induced EMT. We are also defining how MMP/ROS induce cellular aneuploidy and mitotic abnormalities through stimulation of centrosome amplification.