Bufalin suppresses breast cancer bone metastasis through targeting SEC13-mediated osteoclastogenesis

Bone is the most common metastatic site in Breast cancer, where osteoclast activation contributes to osteolytic destruction. Bufalin (BU) has shown anti-tumor activity in several cancers, but its effects on breast cancer bone metastasis remain unclear.

This study aimed to investigate whether BU suppresses breast cancer-induced osteoclast differentiation and osteolytic bone metastasis, and to explore its underlying mechanism.

In vivo murine models of breast cancer bone metastasis were used to evaluate the effects of BU on metastatic progression. Osteoclast differentiation and resorptive function were assessed using in vitro and in vivo assays. Biochemical, biophysical, and genetic approaches were employed to identify and validate the direct molecular target of Bu, and downstream signaling pathways regulating osteoclastogenesis were investigated. The clinical relevance of SEC13 (SEC13 homolog, nuclear pore and COPII coat complex component) was analyzed using breast cancer tissue specimens and patient outcome data. Potential combinatorial effects of BU with the RANKL inhibitor denosumab were also briefly evaluated.

BU markedly suppressed bone metastasis and inhibited tumor-induced osteoclastogenesis. SEC13 was identified as a molecular target associated with BU treatment and was highly expressed in breast cancer tissues, correlating with poor clinical outcomes. Genetic ablation or pharmacological inhibition of SEC13 in tumor cells significantly reduced osteoclast differentiation and metastatic burden. Mechanistically, SEC13 promoted osteoclastogenesis via HMGB1 release and subsequent activation of the TLR4/NF-κB signaling axis in the bone microenvironment, a process effectively disrupted by BU. Notably, combined treatment with BU further strengthened the suppressive effects of denosumab on osteoclast differentiation and bone metastasis.

BU demonstrates potent pharmacological activity against breast cancer bone metastasis by targeting SEC13 and suppressing tumor-induced osteoclast differentiation. This effect is mediated through inhibition of HMGB1 release and blockade of the TLR4/NF-κB signaling axis, leading to reduced osteoclast formation and inhibition of metastatic progression.