Grant: Operating Grant

. Death from cancer mainly occurs after cancer growth (carcinogenesis) by spreading (metastasis). In breast cancer the tissue is dissolved by enzymes termed "proteases" causing malignant cells to spread and then enter blood vessels and finally go to organs like lung. We found that highly malignant breast cancer cells make important proteases called matrix metalloproteinases (MMPs) and others called "matriptases". We discovered that these proteases do much more than just dissolve tissue. By cutting signaling molecules they act like molecular cell phones: the cancer cell changes its behaviour, usually for the worse. We first developed new techniques (gene chips and "proteomics") to identify 1000s of proteases and dissolved proteins and so obtain an overall picture of the disease. Doing so uncovers the different changes as proteolytic signatures that occur in breast and lung cancer. Our proteomics methods specifically uncover the dissolved proteins and by knowing these we can decipher the circuits that proteases use to "call in" on tumors, making them more cancerous. The dissolved protein stubs also form important telltale signs of cancer called biomarkers. Tumors in mouse mammary glands are a good model for human breast cancer. We found certain proteases that are only in those primary tumors in mice that spread. It is important to know what they do at this stage in helping cancer grow and spread. Some of the proteins cut by these key proteases might become tumor biomarkers to help diagnosis and others identify the ways the body prevents cancer.