Isotoosendanin exerts inhibition on triple-negative breast cancer through abrogating TGF- β -induced epithelial-mesenchymal transition via directly targeting TGF β R1.

As the most aggressive breast cancer, triple-negative breast cancer (TNBC) is still incurable and very prone to metastasis. The transform growth factor β (TGF- β )-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- β -induced EMT and the formation of invadopodia. ITSN can directly interact with TGF- β receptor type-1 (TGF β R1) and abrogated the kinase activity of TGF β R1, thereby blocking the TGF- β -initiated downstream signaling pathway. Moreover, the ITSN-provided inhibition on metastasis obviously disappeared in TGF β R1-overexpressed TNBC cells in vitro as well as in mice bearing TNBC cells overexpressed TGF β R1. Furthermore, Lys232 and Asp351 residues in the kinase domain of TGF β R1 were found to be crucial for the interaction of ITSN with TGF β R1. Additionally, ITSN also improved the inhibitory efficacy of programmed cell death 1 ligand 1 (PD-L1) antibody for TNBC in vivo via inhibiting the TGF- β -mediated EMT in the tumor microenvironment. Our findings not only highlight the key role of TGF β R1 in TNBC metastasis, but also provide a leading compound targeting TGF β R1 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 TGF β R1 inhibitor.