Epithelial-Mesenchymal Transition in Breast Cancer

Matrix metalloproteinases (MMPs) are essential for many physiological processes, but their inappropriate expression can facilitate the development and progression of tumors.

Recognition of the relationship between matrix metalloproteinases 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 preliminary data show that exposure of mammary epithelial cells to selected matrix metalloproteinases causes cleavage of a cell surface molecule that stimulates cellular production of reactive oxygen species (ROS). MMP-dependent production of reactive oxygen species causes cells to undergo epithelial-mesenchymal transitionm, which is a fundamental phenotypic alteration associated with progression to metastasis, and compromises the cellular genomic stability.

Our lab is investigating the specific steps associated with the MMP-induced malignant transformation in breast cancer to determine potential points for therapeutic intervention.

We're working to identify the proteolytic target of matrix metalloproteinases that stimulates the development of reactive oxygen species. We're 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 epithelial-mesenchymal transition. Our team is also defining how MMP-dependent production of ROS induces cellular aneuploidy and mitotic abnormalities through stimulation of centrosome amplification.