Abstract
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.
Highlights
Inflammatory breast cancer (IBC) is a rare and aggressive form of invasive breast cancer accounting for 2–4%, or about 4,000 breast cancer cases annually in the United States
We hypothesized that a prerequisite for matriptase and c-Met to be functionally linked in vivo is that they are expressed in close proximity to each other, on either the same cell or neighboring cells
An important component to elucidate the roles of matriptase and c-Met in inflammatory breast cancer (IBC) is to determine their expression and localization in IBC patient samples and IBC cultured cells
Summary
Inflammatory breast cancer (IBC) is a rare and aggressive form of invasive breast cancer accounting for 2–4%, or about 4,000 breast cancer cases annually in the United States. IBC is characterized by rapid progression, local and distant metastases, younger age of onset, and lower overall survival compared with other breast cancers, with a 5-year survival rate of 25–40% when treated with neoadjuvant chemotherapy, mastectomy, and postmastectomy radiation. 20–40% of IBC cases are triple-negative breast cancers (TNBC) which excludes hormone therapy and HER2 targeting as treatment options [1,2,3]. Extracellular proteases have long been associated with cancer progression because of their ability to degrade extracellular matrices, which promotes invasion and metastasis. This view has been expanded with the findings that proteolysis regulates multiple steps of tumor progression including proliferation, differentiation, apoptosis, and invasion. One concept in protease mechanistic research is that proteolytic modifications of targets, including activation of growth factors, are critically involved in carcinogenesis through activation of oncogenic signaling pathways
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