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The poor prognosis for patients with inflammatory breast cancer (IBC) compared to patients with other types of breast cancers emphasizes the need to better understand the molecular underpinnings of this disease with the goal of developing effective targeted therapeutics. Dysregulation of matriptase expression, an epithelial-specific member of the type II transmembrane serine protease family, has been demonstrated in many different cancer types. To date, no studies have assessed the expression and potential pro-oncogenic role of matriptase in IBC. We examined the functional relationship between matriptase and the HGF/c-MET signaling pathway in the IBC cell lines SUM149 and SUM190, and in IBC patient samples. Matriptase and c-Met proteins are localized on the surface membrane of IBC cells and their expression is strongly correlated in infiltrating cancer cells and in the cancer cells of lymphatic emboli in patient samples. Abrogation of matriptase expression by silencing with RNAi or inhibition of matriptase proteolytic activity with a synthetic inhibitor impairs the conversion of inactive pro-HGF to active HGF and subsequent c-Met-mediated signaling, leading to efficient impairment of proliferation and invasion of IBC cells. These data show the potential of matriptase inhibitors as a novel targeted therapy for IBC, and lay the groundwork for the development and testing of such drugs.

Matriptase is an epithelia-specific membrane-anchored serine protease that has received considerable attention in recent years because of its consistent dysregulation in human epithelial tumours, including breast cancer. Mice with reduced levels of matriptase display a significant delay in oncogene-induced mammary tumour formation and blunted tumour growth. The abated tumour growth is associated with a decrease in cancer cell proliferation. Here we demonstrate by genetic deletion and silencing that the proliferation impairment in matriptase-deficient breast cancer cells is caused by their inability to initiate activation of the c-Met signalling pathway in response to fibroblast-secreted pro-HGF. Similarly, inhibition of matriptase catalytic activity using a selective small-molecule inhibitor abrogates the activation of c-Met, Gab1 and AKT, in response to pro-HGF, which functionally leads to attenuated proliferation in breast carcinoma cells. We conclude that matriptase is critically involved in breast cancer progression and represents a potential therapeutic target in breast cancer.

A study was conducted to show that matriptase possesses a strong oncogenic potential when unopposed by its endogenous inhibitor, HAI-1. It can be concluded that matriptase induced activation was frequently accompanied by H-ras and K-ras mutations in carcinogen-induced tumors, whereas matriptase-induced spontaneous carcinoma formation occurred independently of ras activation.

The uptake and lysosomal degradation of collagen by fibroblasts constitute a major pathway in the turnover of connective tissue. However, the molecular mechanisms governing this pathway are poorly understood. Here, we show that the urokinase plasminogen activator receptor-associated protein (uPARAP)/Endo180, a novel mesenchymally expressed member of the macrophage mannose receptor family of endocytic receptors, is a key player in this process. Fibroblasts from mice with a targeted deletion in the uPARAP/Endo180 gene displayed a near to complete abrogation of collagen endocytosis. Furthermore, these cells had diminished initial adhesion to a range of different collagens, as well as impaired migration on fibrillar collagen. These studies identify a central function of uPARAP/ Endo180 in cellular collagen interactions.

Results demonstrate that mouse glandular kallikrein mGK-6 acts as a proform of the key enzyme urokinase-type plasminogen activator (pro-uPA) in vivo. Data further indicate that as mGK-6 is found in many tissues and plasma, it can be considered as physiological pro-uPA activator at other sites.

Pericellular proteases have long been implicated in carcinogenesis. Previous research focused on these proteins, primarily as extracellular matrix ( ECM) protein-degrading enzymes which allowed cancer cells to breach the basement membrane and invade surrounding tissue. However, recently, there has been a shift in the view of cell surface proteases, including serine proteases, as proteolytic modifiers of particular targets, including growth factors and protease-activated receptors, which are critical for the activation of oncogenic signaling pathways. Of the 176 human serine proteases currently identified, a subset of 17, known as type II transmembrane serine proteases ( TTSPs). Many have been shown to be relevant to cancer progression since they were first identified as a family around the turn of the century. To this end, altered expression of TTSPs appeared as a trademark of several tumor types. However, the substrates and underlying signaling pathways remained unclear. Localization of these proteins to the cell surface places them in the unique position to mediate signal transduction between the cell and its surrounding environment. Many of the TTSPs have already been shown to play key roles in processes such as postnatal development, tissue homeostasis, and tumor progression, which share overlapping molecular mechanisms. In this review, we summarize the current knowledge regarding the role of the TTSP family in pro-oncogenic signaling. [ABSTRACT FROM AUTHOR]