title: Targeting matriptase in breast cancer abrogates tumour progression via impairment of stromal-epithelial growth factor signalling.
abstract: 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.
authors: 1] Department of Pharmacology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, 540 E Canfield, Scott Hall Room 6332, Detroit, Michigan 48201, USA [2] Department of Oncology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, 540 E Canfield, Scott Hall Room 6332, Detroit, Michigan 48201, USA [3] Cancer Biology Graduate Program, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, 110 E. Warren Avenue, Suite 2215, Detroit, Michigan 48201, USA.
authors: Gina L
authors: GL
authors: Zoratti
authors: Department of Pharmacology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, 540 E Canfield, Scott Hall Room 6332, Detroit, Michigan 48201, USA.
authors: Lauren M
authors: LM
authors: Tanabe
authors: Department of Pharmacology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, 540 E Canfield, Scott Hall Room 6332, Detroit, Michigan 48201, USA.
authors: Fausto A
authors: FA
authors: Varela
authors: 1] Department of Pharmacology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, 540 E Canfield, Scott Hall Room 6332, Detroit, Michigan 48201, USA [2] Department of Oncology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, 540 E Canfield, Scott Hall Room 6332, Detroit, Michigan 48201, USA [3] Cancer Biology Graduate Program, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, 110 E. Warren Avenue, Suite 2215, Detroit, Michigan 48201, USA.
authors: Andrew S
authors: AS
authors: Murray
authors: Department of Pharmacology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, 540 E Canfield, Scott Hall Room 6332, Detroit, Michigan 48201, USA.
authors: Christopher
authors: C
authors: Bergum
authors: Department of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001 12e Av Nord, Sherbrooke, Quebec J1H 5N4, Canada.
authors: Éloïc
authors: É
authors: Colombo
authors: Department of Surgery, Norris Comprehensive Cancer Center, University of Southern California, 1510 San Pablo Street, Suite 412, Los Angeles, California 90033, USA.
authors: Julie E
authors: JE
authors: Lang
authors: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Room 211, Bethesda, Maryland 20892, USA.
authors: Alfredo A
authors: AA
authors: Molinolo
authors: Department of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001 12e Av Nord, Sherbrooke, Quebec J1H 5N4, Canada.
authors: Richard
authors: R
authors: Leduc
authors: Department of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001 12e Av Nord, Sherbrooke, Quebec J1H 5N4, Canada.
authors: Eric
authors: E
authors: Marsault
authors: Department of Oncology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, 540 E Canfield, Scott Hall Room 6332, Detroit, Michigan 48201, USA.
authors: Julie
authors: J
authors: Boerner
authors: 1] Department of Pharmacology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, 540 E Canfield, Scott Hall Room 6332, Detroit, Michigan 48201, USA [2] Department of Oncology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, 540 E Canfield, Scott Hall Room 6332, Detroit, Michigan 48201, USA [3] Cancer Biology Graduate Program, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, 110 E. Warren Avenue, Suite 2215, Detroit, Michigan 48201, USA.
authors: Karin
authors: K
authors: List
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D005260:Female; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010750:Phosphoproteins; D011498:Protein Precursors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met; D012697:Serine Endopeptidases / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C098587:GAB1 protein, human; C490897:Gab1 protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D011498:Protein Precursors; C086013:pro-hepatocyte growth factor; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D012697:Serine Endopeptidases; C485596:ST14 protein, human; C118992:St14 protein, mouse