title: Matriptase regulates c-Met mediated proliferation and invasion in inflammatory breast cancer.
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.
authors.affiliation: Department of Oncology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA.|Department of Pharmacology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA.
authors.forename: Gina L
authors.initials: GL
authors.lastname: Zoratti
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Tanabe
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hyland
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Duhaime
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H5N4 Canada.
authors.forename: Éloïc
authors.initials: É
authors.lastname: Colombo
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H5N4 Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Leduc
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H5N4 Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Marsault
authors.affiliation: Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington, DC 20057, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Johnson
authors.affiliation: Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington, DC 20057, USA.
authors.forename: Chen-Yong
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Department of Oncology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Boerner
authors.affiliation: Department of Surgery, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Lang
authors.affiliation: Department of Oncology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA.|Department of Pharmacology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA.
authors.forename: Karin
authors.initials: K
authors.lastname: List
mesh_terms: D018929:Cell Culture Techniques / Q000379:methods; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D058922:Inflammatory Breast Neoplasms / Q000473:pathology*; D009361:Neoplasm Invasiveness; D011498:Protein Precursors / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C066855:HGF protein, human; D011498:Protein Precursors; D034741:RNA, Small Interfering; C086013:pro-hepatocyte growth factor; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D012697:Serine Endopeptidases; C485596:ST14 protein, human
keywords: inflammatory breast cancer; matriptase; type II transmembrane serine proteases