Bruceine D promotes TNBC regression by inhibiting M2-like tumor-associated macrophage polarization induced Wnt3a/β-catenin pathway

Triple-negative breast Cancer (TNBC) is distinguished by its marked invasiveness and high recurrence rate, making it the subtype of breast Cancer with the most dismal prognosis. Effective treatment modalities for TNBC remains elusive. Tumor-associated macrophages (TAMs) are essential stromal components within the tumor microenvironment, significantly contributing to TNBC progression. Herein, we demonstrated that Bruceine D (BD), a natural quassinoid isolated from Chinese herb Brucea javanica (L.) Merr., diminished the secretion of Wnt3a and downregulated the expression of β-catenin, thereby not only inhibiting the polarization of M2-like macrophages and enhancing the ratio of M1/M2 macrophage but also suppressing M2-like macrophage-promoted proliferation and metastasis of tumor cells. Importantly, BD impeded the polarization of infiltrating M2-like TAMs and inhibited the Wnt3a/β-catenin signaling in tumors, consequently suppressing tumor growth and the formation of metastatic lesions in the lungs and livers of TNBC-bearing mice. This study highlights the promising therapeutic potential of BD in remodeling TAMs as a strategy to address TNBC.

Bruceine D; Metastasis; Triple-negative breast cancer; Tumor-associated macrophages; Wnt3a/β-catenin.