Role of Matrix Metalloproteinases and Their Tissue Inhibitors in Human Breast Adenocarcinoma

摘要

The deadly consequences of breast cancer are due to metastasis, a process in which tumor cells penetrate the blood vessels and enter other tissues to spread the cancer. This movement through vessels and tissues is attributed to a group of digestive enzymes (the matrix metalloproteinases or MMPs) that can destroy the matrix in advance of tumor cell movement. These MMPs are normally produced in small amount and are held in check by inhibitors in the tissues (tissue inhibitors of MMPs or TIMPs). We took 160 samples of breast tissues (benign tumors and various carcinomas) and measured the production of six different MMPs and 2 TIMPs in a unified multipronged approach. We used antibody methods to see which cells are producing these enzymes and inhibitors. The most prominent enzyme was MMP-9, also known as gelatinase B, which is able to break down the wall that forms around tumor cell clusters. While this, and other MMPs were elevated in cancer, the TIMP inhibitors were produced at levels well below normal. This results in an imbalance in which the destructive proteases greatly outweigh the controlling inhibitors, facilitating the spread of the cancer. Biochemical quantification of MMPs by zymography showed an overall increase in all types of MMPs in cancer tissues. MMP-9 was the key MMP; it was present at levels 0.39 (in situ ductal) to 4.8 (infiltrating ductal) micronmeter wet weight tissue in cancer tissues compared to unquantifiable amounts in normal (3/6) and benign neoplasm (25/30) tissues. Zymography also showed a fraction of MMP-9 and MMP-2 in their active forms in high grade breast cancers compared to normal and benign tissues Reverse zymography showed the presence of TIMPs - l,-2 and - 3 in all breast tissues.