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DOI: 10.1055/s-0034-1388555
Knockdown of TRAIL-R2 in breast cancer cells impairs bone metastases formation in a preclinical mouse model
Introduction: Plasma-membrane localized death receptors TRAIL-R1/R2 induce apoptosis and pro-inflammatory responses when crosslinked by their ligand TRAIL. In its nuclear localization TRAIL-R2 promotes cell proliferation by regulating the maturation of miRNA let-7. Interestingly, overexpression of TRAIL-R2 has been correlated with worse prognosis for patients with breast cancer, which is known to frequently metastasize to the bone. In the present study, using a preclinical mouse model, we analyzed the impact of TRAIL-R2 on the ability of breast cancer cells to form bone metastases.
Methods: Bone seeking MDA-MB-231-cells were transfected with TRAIL-R2-shRNA and intracardially injected in SCID-beige-mice. In vivo imaging of the bone metastases was performed by bioluminescence, MRI and µCT-analysis. Characterization of the cell-phenotype was accomplished in vitro by using Western-Blotting, ELISA and migration assays.
Results: The knockdown of TRAIL-R2 strongly diminished the frequency of bone metastases in breast cancer cells. No difference was detected in the osteolytic bone loss by µ-CT. The cells exhibit a mixed EMT-phenotype and an inhibited migration towards SDF1.
Conclusion: TRAIL-R2 plays an important role in the capability of breast cancer cells to form bone metastases. It therefore might display a critical target in the multimodal therapy of breast cancer in advanced tumor stages.