NOVEL MEMBRANE TYPE-1 MATRIX METALLOPROTEASE INHIBITOR EFFECT ON PREMALIGNANT BREAST EPITHELIAL CELL PHENOTYPE

摘要

Invasive cancer is generally associated with aberrant protease trafficking, invasion and metastasis. Membrane type-1 matrix metalloprotease (MT1-MMP), an enzyme active upon many constituents of the extracellular matrix (ECM) and other precursor matrix metalloproteases (MMPs), is usually found on the invading front and is now strongly associated with a loss of epitheliod polarity and the acquisition of an increased migratory and invasive phenotype. Though only active for a short while, MT1-MMP seems to play a major role in invasion, giving rise to prolonged effects by processing cell adhesion molecules, such as integrins and CD442, initiating a mesenchymal-like loss of polarity and triggering invasion. An immortal (9p21-/-), non-invasive, polar and otherwise normal, MCF-10A breast epithelial cell line and its invasive, nonpolar, mesenchymal-like c-Ha-ras(V12)-transfected MCF-10AneoT derivative, in which transfection results in a loss of apical-basolateral polarity and acquisition of an elongated, mesenchymal, invasive phenotype1, is a suitable model for studying the possible role of aberrant MT1-MMP trafficking in epithelial to mesenchymal transition and the effect of blocking MT1-MMP activity on polarity and invasion. TF22d, a novel azauracil MT1-MMP inhibitor, was designed to be less toxic than previous MMP inhibitors and target MT1-MMP with greater affinity. The aim of this study was to determine the effects of TF22d on MT1-MMP-dependent premalignant cell migration and phenotype, after assessing potential toxicity.