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.
Highlights
TNF-related apoptosis inducing ligand receptor (TRAIL-R) 1 and 2, both members of the TNF receptor superfamily, are able to induce both apoptotic and nonapoptotic signaling when cross-linked at the plasma membrane by their cognate ligand TRAIL [1,2,3,4]
We demonstrate that the knockdown of TRAIL-R2 in these cells down regulates the levels of bone metastasis-related proteins HMGA2, p-Src and C-X-C chemokine receptor 4 (CXCR4), leads to the re-expression of E-cadherin, and dramatically impairs the capability of cells to metastasize to the bone
Because FACS analyses showed no significant changes in www.impactjournals.com/oncotarget the expression of TRAIL-R1, either at the cell surface or intracellularly, these results suggest that TRAIL-R2 may play a role in promoting breast cancer bone metastasis
Summary
TNF-related apoptosis inducing ligand receptor (TRAIL-R) 1 and 2, both members of the TNF receptor superfamily, are able to induce both apoptotic and nonapoptotic signaling when cross-linked at the plasma membrane by their cognate ligand TRAIL [1,2,3,4]. A variety of tumors overexpress these death receptors, and for some, high expression of primarily TRAIL-R2, and TRAIL-R1, has been associated with a poor prognosis [9,10,11,12,13,14,15,16,17,18,19,20] This observation may reflect the pro-tumoral signaling of membrane-bound TRAIL receptors in response to TRAIL present in the tumor microenvironment. More critical evaluations of immunohistochemical staining revealed mainly intracellular distribution of TRAIL death receptors in tumor tissues (for review see [20]) Such intracellular locations, either in the cytoplasm or in the nucleus, have been mainly regarded as hide-outs for these receptors, representing a strategy for cancer cells to resist TRAILmediated apoptosis [24, 25]. The intracellular sequestering of TRAIL receptors could potentially represent an escape mechanism of tumor cells from immune surveillance
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