Abstract
Purpose
Bone metastasis in breast cancer has been linked to activity of c-Src kinase, one of the extensively explored tyrosine kinases in cell biology. The impact of TNF-related apoptosis inducing ligand (TRAIL) and TRAIL receptors has just recently been integrated into this conception.
Methods
An osteotropic clone of MDA-MB-231 cells simulated a model for bone metastasis of triple-negative breast cancer (TNBC). The effects of Dasatinib, a clinically established inhibitor of Src kinases family and Abl were evaluated in vitro and in vivo. In vivo effects of Dasatinib treatment on the occurrence of skeletal metastases were tested in a xenograft mouse model after intra-cardiac injection of osteotropic MDA-MB-231-cells. Ex vivo analyses of the bone sections confirmed intraosseous growth of metastases and allowed determination of osteoclastic activity.
Results
Treatment of osteotropic MDA-MB-231 cells with Dasatinib inhibited proliferation rates in vitro. A shift in TRAIL-receptor expression towards an induction of oncogenic TRAIL-R2 was observed. In vivo, 15 of 30 mice received an intra-peritoneal treatment with Dasatinib. These mice showed significantly less skeletal metastases in bioluminescence scans. Moreover, a pronounced increase in bone volume was observed in the treatment group, as detected by µ-Computed Tomography. Dasatinib treatment also led to a greater increase in bone density in tibiae without metastatic affection, which was accompanied by reduced recruitment of osteoclasts.
Conclusion
Our observations support the concept of utilizing Dasatinib in targeting early-stage bone metastatic TNBC and sustaining bone health.
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Acknowledgements
The authors are grateful to Gabriele Trompke for her technical assistance.
Funding
Christian Schem received project-related “start up funding for young investigators” from the Medical faculty of Kiel University in 2015, No F355918.
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TH: project development, data collection or management, data analysis, manuscript writing; ALR: data collection or management, data analysis, manuscript editing; MR: data collection or management, data analysis; MT: data collection or management, data analysis; OW: data collection or management, data analysis; TD: data collection or management, data analysis; CB: data analysis; NM: project development, manuscript editing; CCG: manuscript editing; ST: data collection or management, data analysis, manuscript editing; AT: project development, data collection or management, data analysis, manuscript editing; CS: project development, data collection or management, data analysis, manuscript editing.
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All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted (Ethics Committee for Animal Experiments at Christian‐Albrechts‐Universität‐zu‐Kiel, V 242—64202/2015 (73-6/15)).
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Heilmann, T., Rumpf, AL., Roscher, M. et al. Dasatinib prevents skeletal metastasis of osteotropic MDA-MB-231 cells in a xenograft mouse model. Arch Gynecol Obstet 301, 1493–1502 (2020). https://doi.org/10.1007/s00404-020-05496-4
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DOI: https://doi.org/10.1007/s00404-020-05496-4