Matrix metalloproteinases in the process of invasion and metastasis of breast cancer

Metastatic cascade in malignant tumors, including breast cancer, starts with localized invasion of the host tissue. This process, requiring that tumor cells separate from each other, includes loss of homotypic and heterotypic cell adhesion and cell-cell contact inhibition, acquisition of motility, exacerbated by “epithelial-to-mesenchymal transition”, and production of proteolytic enzymes which degrade basal membrane and extracellular matrix. In this sense, aside from urokinase type plasminogen activator, increased expression and activity of matrix metalloproteinases (MMPs) is one of the earliest and most sustained events in tumor progression, playing a role in angiogenesis, invasion and metastasis. MMPs are a family of 23 zinc metalloproteinases, secreted as latent pro-enzymes, activated by proteolytic cleavage, and inhibited by the tissue inhibitors of metalloproteinases. The most commonly connected MMPs with the processes of metastasis are MMP-2 (gelatinase A) and MMP-9 (gelatinase B), due to their ability to degrade collagen type IV, major component of vascular basement membrane. MMP-2 and MMP-9 are also required for the switch to the “angiogenic phenotype” during tumor progression and activation of dormant tumor cells. The association of the increase in serum MMP-2 and MMP-9 activity and clinical stage suggests the usefulness of these parameters as markers in the follow-up and prognosis of breast cancer patients. The concept of “stromal-directed therapy” of cancer, with MMPinhibitors directed against MMPs as targets, is based on the observed MMP up-regulation in tumors.