Metalloproteinases: role in breast carcinogenesis, invasion and metastasis

The MMPs, which are also known as matrixins, are a family of structurally and functionally related endoproteinases that are involved in the degradation of the extracellular matrix (ECM). Physiologically, these enzymes play a role in normal tissue remodelling events such as embryonic development, angiogenesis, ovulation, mammary gland involution and wound healing. Abnormal expression appears to contribute to various pathological processes including rheumatoid arthritis and osteoarthritis, pulmonary emphysema, and tumour growth, invasion and metastasis (for review [1**]). Currently, at least 19 different MMPs are known to exist in mammalian systems.The main characteristics of these proteinases have previously been described in detail [1**,2**], and are therefore only briefly mentioned here. All MMPs possess specific domains that are conserved between different members. Catalytic activity depends on the presence of zinc ions at the catalytic active site. Most MMPs are synthesized and secreted in a zymogen form. Activation is usually accompanied by loss of a 10-kDa amino-terminal domain. Most cleave at least one component of the ECM. Finally, proteolytic activity is inhibited by tissue inhibitors known as tissue inhibitors of metalloproteinase (TIMPs).Based on in vitro substrate specificity and domain structure, the MMPs have traditionally been divided into four main subgroups: the interstitial collagenases, gelatinases, stromelysins and membrane MMPs [1**,2**]. The collagenases comprise interstitial collagenase (MMP-1), neutrophil collagenase (MMP-8) and collagenase 3 (MMP-13). These MMPs catalyze degradation of fibrillar forms of collagen (ie types I, II and III). MMP-1 shows a preference for the type III form, MMP-8 preferentially degrades type I collagen, and MMP-13 has highest affinity for type II collagen [3].The gelatinases, which are also known as type IV collagenases, degrade gelatin (denatured collagen), and types IV, V, VII, IX and X collagen. Type IV collage