title: TRAIL-R2 promotes skeletal metastasis in a breast cancer xenograft mouse model.
abstract: Despite improvements in detection, surgical approaches and systemic therapies, breast cancer remains typically incurable once distant metastases occur. High expression of TRAIL-R2 was found to be associated with poor prognostic parameters in breast cancer patients, suggesting an oncogenic function of this receptor. In the present study, we aimed to determine the impact of TRAIL-R2 on breast cancer metastasis. Using an osteotropic variant of MDA-MB-231 breast cancer cells, we examine the effects of TRAIL-R2 knockdown in vitro and in vivo. Strikingly, in addition to the reduced levels of the proliferation-promoting factor HMGA2 and corresponding inhibition of cell proliferation, knockdown of TRAIL-R2 increased the levels of E-Cadherin and decreased migration. In vivo, these cells were strongly impaired in their ability to form bone metastases after intracardiac injection. Evaluating possible underlying mechanisms revealed a strong downregulation of CXCR4, the receptor for the chemokine SDF-1 important for homing of cancers cells to the bone. In accordance, cell migration towards SDF-1 was significantly impaired by TRAIL-R2 knockdown. Conversely, overexpression of TRAIL-R2 upregulated CXCR4 levels and enhanced SDF-1-directed migration. We therefore postulate that inhibition of TRAIL-R2 expression could represent a promising therapeutic strategy leading to an effective impairment of breast cancer cell capability to form skeletal metastases.
authors.affiliation: Division of Molecular Oncology, Institute for Experimental Cancer Research, CCC-North, University of Kiel, Kiel, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Fritsche
authors.affiliation: Division of Molecular Oncology, Institute for Experimental Cancer Research, CCC-North, University of Kiel, Kiel, Germany.|Department of Gynecology, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Heilmann
authors.affiliation: Section Biomedical Imaging, Department of Radiology and Neuroradiology, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Tower
authors.affiliation: Clinic for General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Hauser
authors.affiliation: Department of Tumor Cell Biology, University Hospital of Surgery, Heidelberg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: von Au
authors.affiliation: Division of Molecular Oncology, Institute for Experimental Cancer Research, CCC-North, University of Kiel, Kiel, Germany.
authors.forename: Doaa
authors.initials: D
authors.lastname: El-Sheikh
authors.affiliation: Section Biomedical Imaging, Department of Radiology and Neuroradiology, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Graeme M
authors.initials: GM
authors.lastname: Campbell
authors.affiliation: Division of Molecular Oncology, Institute for Experimental Cancer Research, CCC-North, University of Kiel, Kiel, Germany.
authors.forename: Göhkan
authors.initials: G
authors.lastname: Alp
authors.affiliation: Department of General Pediatrics, ALL-BFM Study Group, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Denis
authors.initials: D
authors.lastname: Schewe
authors.affiliation: Division of Molecular Oncology, Institute for Experimental Cancer Research, CCC-North, University of Kiel, Kiel, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hübner
authors.affiliation: Section Biomedical Imaging, Department of Radiology and Neuroradiology, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Tiwari
authors.affiliation: Division of Molecular Oncology, Institute for Experimental Cancer Research, CCC-North, University of Kiel, Kiel, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kownatzki
authors.affiliation: Section Biomedical Imaging, Department of Radiology and Neuroradiology, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Susann
authors.initials: S
authors.lastname: Boretius
authors.affiliation: Institute of Immunology, University of Kiel, Kiel, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Adam
authors.affiliation: Department of Gynecology, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Jonat
authors.affiliation: Clinic for General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Becker
authors.affiliation: Section Biomedical Imaging, Department of Radiology and Neuroradiology, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Claus C
authors.initials: CC
authors.lastname: Glüer
authors.affiliation: Department of Tumor Cell Biology, University Hospital of Surgery, Heidelberg, Germany.
authors.forename: Margot
authors.initials: M
authors.lastname: Zöller
authors.affiliation: Division of Molecular Oncology, Institute for Experimental Cancer Research, CCC-North, University of Kiel, Kiel, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Kalthoff
authors.affiliation: Department of Gynecology, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schem
authors.affiliation: Division of Molecular Oncology, Institute for Experimental Cancer Research, CCC-North, University of Kiel, Kiel, Germany.|Clinic for General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Trauzold
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000556:secondary*; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics; D002277:Carcinoma / Q000235:genetics / Q000556:secondary*; D002455:Cell Division; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000502:physiology; D002633:Chemotaxis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D025743:HMGA2 Protein / Q000096:biosynthesis / Q000235:genetics; D064593:Heterografts; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009928:Organ Specificity; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000473:pathology*
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D015820:Cadherins; D054377:Chemokine CXCL12; D025743:HMGA2 Protein; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: CXCR4; TRAIL-R2; bone homing; bone metastasis; breast cancer