This program focusses on characterization of structure and function of a new extracellular matrix-degrading enzyme in breast cancer. The malignant behavior of breast cancer is thought to proceed in a stepwise fashion known as malignant progression. Malignant progression seems to depend on genetic instability, disregulated proliferation, and a breakdown of stromal- epithelial compartmentalization resulting in metastases. Breast tumor metastases are proposed to depend upon attachment of cancer cells to the basement membrane and stromal matrix proteins, local proteolytic degradation of these proteins, a highly motile cellular phenotype, and the ability to colonize a distant site of the host. Evidence has accumulated that important proteases in the metastatic process include metalloproteinases, serine, cysteine, and aspartyl proteinases. Of these, most of the evidence to date in early stages of breast cancer metastases implicates metalloproteinases; both 72kDa and 92kDa species have been described in breast cancer. These enzymes are secreted in latent form, associated with endogenous inhibitors known as the TIMPs (tissue inhibitors of metalloproteinase). The role of these enzymes is puzzling since they require a poorly defined process of local activation and they degrade native collagen IV with much less activity than gelatin (denatured collagen). We have described and isolated an apparently new metalloproteinase from breast cancer cell lines. this enzyme is secreted as a complex approximately 80 kDa in size, is characterized by novel metal and pH dependence, appears to be secreted in active form and does not appear to be inhibited by TIMP-2. In addition, the 80kDa metalloproteinase degrades native Type IV collagen, gelatin, laminin, and fibronectin. The current proposal is focussed on better understanding the role of this enzyme in breast cancer metastases. We will define its hormonal regulation, association with malignant progression and involvement in tumor-basement membrane and tumor-vasculature interactions. Its structure will be more completely elucidated, and inhibitors explored for therapeutic use in suppression of breast tumor growth and/or metastases. Antibodies will also be prepared for its detection in breast tumor biopsies and for characterization of its expression in comparison to other proteases and tumor characteristics. Study of this very active breast tumor protease may lead to improved breast cancer prognostication and therapy.
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