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

Hendrik Fritsche, Thorsten Heilmann, Robert J. Tower, Charlotte Hauser, Anja von Au, Doaa El-Sheikh, Graeme M. Campbell, Göhkan Alp, Denis Schewe, Sebastian CHübner, Sanjay Tiwari, Daniel Kownatzki, Susann Boretius, Dieter Adam, Walter Jonat, Thomas Becker, Claus C. Glüer, Margot Zöller, Holger Kalthoff, Christian SchemAnna Trauzold

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)9502-9516
Number of pages15
JournalOncotarget
Volume6
Issue number11
DOIs
StatePublished - 2015
Externally publishedYes

Keywords

  • Bone homing
  • Bone metastasis
  • Breast cancer
  • CXCR4
  • TRAIL-R2

ASJC Scopus subject areas

  • Oncology

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