Electronic Thesis and Dissertation Repository


Master of Science




Dr. Sashko Damjanovski


Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a multifunctional protease that invokes changes extracellularly via cleavages of ECM substrates, and intracellularly through induction of cell signalling cascades, both to influence cell behaviour and motility. The effects of MT1-MMP activation, MMP catalytic activity, and ERK1/2 signalling were examined by chemically or genetically altering each parameter. Regardless of treatment, expression of the two gelatinases, MMP-2 and -9, were always altered in an inverse relationship. This work proposes a pathway through active MT1-MMP initiation of ERK1/2 phosphorylation and subsequent targeting the NF-κB transcription factor, to ultimately influence MMP-9 expression. Modulation of MT1-MMP activation, activity, or downstream signalling, all resulted in decreased invasive potential in MDA-MB-231 breast cancer cells. In a chicken embryo tumour model, only untreated MDA-MB-231 cells resulted in tumour vascularization and complete wound closure. Furthermore, these results suggest that cells lacking active MT1-MMP, phospho-ERK1/2, or adequate MMP-9, have considerably reduced invasive potential.