TRAIL-R2 promotes skeletal metastasis in a breast cancer xenograft mouse model.

// Hendrik Fritsche 1, * , Thorsten Heilmann 1, 2, * , Robert J. Tower 3, * , Charlotte Hauser 4 , Anja von Au 5 , Doaa El-Sheikh 1 , Graeme M. Campbell 3 , Gohkan Alp 1 , Denis Schewe 6 , Sebastian Hubner 1 , Sanjay Tiwari 3 , Daniel Kownatzki 1 , Susann Boretius 3 , Dieter Adam 7 , Walter Jonat 2 , Thomas Becker 4 , Claus C. Gluer 3 , Margot Zoller 5 , Holger Kalthoff 1 , Christian Schem 2, * , Anna Trauzold 1, 4, * 1 Division of Molecular Oncology, Institute for Experimental Cancer Research, CCC-North, University of Kiel, Kiel, Germany 2 Department of Gynecology, University Hospital Schleswig-Holstein, Kiel, Germany 3 Section Biomedical Imaging, Department of Radiology and Neuroradiology, University Hospital Schleswig-Holstein, Kiel, Germany 4 Clinic for General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, Kiel, Germany 5 Department of Tumor Cell Biology, University Hospital of Surgery, Heidelberg, Germany 6 Department of General Pediatrics, ALL-BFM Study Group, University Hospital Schleswig-Holstein, Kiel, Germany 7 Institute of Immunology, University of Kiel, Kiel, Germany * These authors have contributed equally to this work Correspondence to: Anna Trauzold, e-mail: atrauzold@email.uni-kiel.de Keywords: TRAIL-R2, breast cancer, CXCR4, bone metastasis, bone homing Received: October 02, 2014      Accepted: February 09, 2015      Published: March 25, 2015 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.