We previously found that cordycepin inhibits the growth and metastasis formation of MDA-MB-231 cells through the Hedgehog pathway but has not validated this in vivo. In this study, we confirmed cordycepin's anti-triple-negative breast cancer (TNBC) effect in nude mice and documented its mechanism. We found that cordycepin reduced the volume and weight of MDA-MB-231 xenografts and affected the expression of proliferation-, apoptosis-, epithelial-mesenchymal transition-, and matrix metalloproteinase-related proteins without side effects. RNA sequencing screening, pathway enrichment, and the protein network interaction analysis revealed enriched pathways and targets mainly concentrated on the Hedgehog pathway and its core components of SHH and GLI2. This indicates that the Hedgehog pathway plays a central role in the cordycepin-mediated regulation of growth and metastasis formation in TNBC. The database analysis of the Hedgehog pathway markers (SHH, PTCH1, SMO, GLI1, and GLI2) revealed that the Hedgehog pathway is activated in breast cancer tissues, and its high expression is not conducive to a patient's survival. Finally, we verified that cordycepin effectively inhibited the Hedgehog pathway in TNBC through Western blotting and immunohistochemistry. This study found that cordycepin could regulate the growth and metastasis formation of TNBC through the Hedgehog pathway in vivo, which provides new insights for targeting and treating breast cancer.
Keywords: Cordyceps militaris; Hedgehog pathway; cordycepin; triple-negative breast cancer.