Isotoosendanin exerts inhibition on triple-negative breast cancer through abrogating TGF--induced epithelial-mesenchymal transition directly targeting TGFR1.

As the most aggressive breast cancer, triple-negative breast cancer (TNBC) is still incurable and very prone to metastasis. The transform growth factor (TGF-)-induced epithelial-mesenchymal transition (EMT) is crucially involved in the growth and metastasis of TNBC. This study reported that a natural compound isotoosendanin (ITSN) reduced TNBC metastasis by inhibiting TGF--induced EMT and the formation of invadopodia. ITSN can directly interact with TGF- receptor type-1 (TGFR1) and abrogated the kinase activity of TGFR1, thereby blocking the TGF--initiated downstream signaling pathway. Moreover, the ITSN-provided inhibition on metastasis obviously disappeared in TGFR1-overexpressed TNBC cells as well as in mice bearing TNBC cells overexpressed TGFR1. Furthermore, Lys232 and Asp351 residues in the kinase domain of TGFR1 were found to be crucial for the interaction of ITSN with TGFR1. Additionally, ITSN also improved the inhibitory efficacy of programmed cell death 1 ligand 1 (PD-L1) antibody for TNBC inhibiting the TGF--mediated EMT in the tumor microenvironment. Our findings not only highlight the key role of TGFR1 in TNBC metastasis, but also provide a leading compound targeting TGFR1 for the treatment of TNBC metastasis. Moreover, this study also points out a potential strategy for TNBC treatment by using the combined application of anti-PD-L1 with a TGFR1 inhibitor.