N-3, a novel synthetic derivative of bifendate, inhibits metastasis of triple-negative breast cancer via decreasing p38-regulated FOXC1 protein stability

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with high invasiveness, metastatic potential, and poor prognosis. Epithelial-mesenchymal transition (EMT) is pivotal in TNBC progression, becoming a promising target for TNBC treatment. Our study evaluated N-3, a novel synthetic bifendate derivative, which inhibited the EMT-associated migration and invasion of MDA-MB-231 and 4T1 TNBC cells. The results were consistent with the suppression of FOXC1 expression and transcriptional activity. Additional studies indicated that N-3 reduced the protein stability of FOXC1 by enhancing ubiquitination and degradation. Moreover, N-3 downregulated p-p38 expression and FOXC1 interaction, decreasing the stability of p38-regulated FOXC1. Further, N-3 blocked TNBC metastasis with an artificial lung metastasis model in vivo, related to FOXC1 suppression and EMT. These results highlight the potential of N-3 as a TNBC metastasis treatment. Therefore, FOXC1 regulation could be a novel targeted therapeutic strategy for TNBC metastasis.

Automated summary

This study evaluated a synthetic bifendate derivative, N-3, for its inhibitory effects on EMT-associated migration and invasion of TNBC cells. It was found that N-3 suppressed FOXC1 expression and transcriptional activity, as well as enhanced FOXC1 ubiquitination and degradation. Additionally, N-3 downregulated p-p38 expression and FOXC1 interaction, leading to decreased stability of p38-regulated FOXC1. Furthermore, N-3 blocked TNBC metastasis through FOXC1 suppression and EMT, highlighting its potential as a TNBC metastasis treatment.