Proteolysis in human breast cancer

Abstract

Background-The process of proteolysis is important at several stages of the metastatic cascade. A balance between the expression of the genes encoding endogenous proteinases and inhibitors exists and when the production of proteinases exceeds that of inhibitors proteolysis occurs. Aims-To determine whether diVerences in the profile and activity of proteinases and inhibitors exist within breast tumour tissue (n = 51), surrounding background breast tissue (n = 43), normal breast tissue from breast reduction mammoplasty operations (n = 10), and cells of the breast cancer cell line, MCF-7. Methods-Proteinase (matrix metalloproteinase 1 (MMP-1), MMP-2, MMP-3, MMP-9, urokinase-type plasminogen activator (uPA), and tissue-type PA (tPA)) and inhibitor (tissue inhibitor of metalloproteinases; TIMP-1 and TIMP-2) expression and proteinase activity were compared using substrate zymography, western blotting, immunohistochemistry, and quenched fluorescent substrate hydrolysis. Breast cancer is the most common cancer in women; it aVects one in 12 women and over 15 000 women die from breast cancer in the UK each year. Tumour invasion and metastasis formation are the primary causes of cancer treatment failure and death. Results-The1 The process of metastasis is a complex cascade of organised, sequential, interrelated steps, including angiogenesis, local invasion, intravasation, and extravasation, 1 many of which require active degradation of the host tissue by proteolytic enzymes. The synthesis, secretion, and catalytic activity of proteinases appears to be tightly regulated and most are secreted as inactive zymogens.2 Highly potent natural proteinase inhibitors also exist, which limit the duration of active proteolysis. Under physiological conditions, the balance between proteolytic degradation and the regulatory inhibition of proteolysis controls normal proteolytic events-for example, tissue remodelling and wound healing. In these situations, only selective enzymes, or a cascade of functionally related proteinases, are produced in response to the signal. However, in certain pathological processes, including cancer, the balance between negative regulation and active proteolysis is disrupted so that proteolysis is no longer constrained. At least four classes of proteinases exist and they are most frequently classified according to their catalytic type. 4 These are the matrix metalloproteinases (MMPs or matrixins), and the serine, aspartic, and cysteine proteinases. 5 The coordinated and synergistic action of these four classes of proteinases can completely degrade all extracellular matrix (ECM) components. 3Of these four classes, the matrix metalloproteinases and the serine proteinase, urokinasetype plasminogen activator (uPA), are most extensively linked to cancer invasion and metastasis. Both the role of the MMP and PA systems in cancer and metastasis and their regulation of these processes have been reviewed previously. 5-8Proteinase expression has been studied extensively in many diVerent human cancers, including bre...

Significance of stromal decorin expression during the progression of breast cancer

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HRPAP20: a novel calmodulin-binding protein that increases breast cancer cell invasion

“…An important characteristic associated with tumor progression is acquisition by cancer cells of the capacity to secrete and/or activate proteases, including MMPs (Reich et al, 1988;Garbett et al, 2000;Przybylowska et al, 2005). Collectively, these enzymes are known to degrade a spectrum of ECM components including other pericellular proteins such as laminin, collagen and fibronectin (Nakajima et al, 1987).…”

“…Collectively, these enzymes are known to degrade a spectrum of ECM components including other pericellular proteins such as laminin, collagen and fibronectin (Nakajima et al, 1987). Substrates of MMPs are not restricted to ECM proteins, but also include growth factor-binding proteins, their receptors, growth factor precursors and cell adhesion molecules (Miyazaki et al, 1994;Suzuki et al, 1997;Garbett et al, 2000). MMP expression often correlates with a poor prognosis.…”