Matrix metalloproteinase-induced malignancy in mammary epithelial cells

Abstract

In development, epithelial-mesenchymal transition (EMT) allows interconnected sheets of epithelial cells to reorganize and to pass into and through the surrounding extracellular matrix (ECM). In cancer, EMT-associated processes facilitate invasive growth and development of metastases. Matrix metalloproteinases (MMPs) are enzymes capable of degrading the ECM and altering cell-cell and cell-ECM interactions. MMPs are upregulated in nearly all tumor types, have been shown to induce EMT in cultured cells, and are involved in the development of tumor formation, invasion, and metastasis. We have identified the induction of Rac1b, an alternatively spliced variant of Rac1, as a key event in MMP-induced EMT. Induction of the Rac1b isoform leads to increased cellular reactive oxygen species (ROS), which causes in turn upregulation of Snail, a transcription factor previously implicated in physiological and pathological EMT. MMP/Rac1b-induced ROS also causes DNA damage and induces genomic instability. These findings reveal a new pathway in which a key element of the tumor microenvironment directly stimulates the phenotypic and genotypic alterations involved in malignant transformation, and provides many opportunities for investigation of therapeutic interventions.