RAD51B-EZH2 axis as a potential therapeutic target for TNBC through cell fate conversion.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with higher histologic grade, poorer prognosis, and fewer treatment options due to the lack of reliable and effective molecular targets. Using a functional approach with the Sleeping Beauty (SB) transposon system, we have identified 64 overlapped candidate driver genes for inducing TNBC formation in Brca1-deficient mice and Fgfr2-mutant mice. Further analysis reveals that Rad51b deficiency leads to the development of tumors with a TNBC phenotype by repressing ERα expression through the recruitment of polycomb repressive complex 2 (PRC2) and subsequent trimethylation of histone H3 lysine 27 in Esr1 promoter region. Mechanistically, the loss of RAD51B upregulated cellular ATP levels, followed by the suppression of the AMP-activated protein kinase (AMPK) pathway and dephosphorylation of the Enhancer of zeste homolog 2 (EZH2) at the Thr311 region, which enhances the assembly of PRC2 to repress expression of Esr1. Inhibition of the RAD51B-EZH2 axis allows the re-expression of functional ERα, making TNBC targetable by endocrine therapy. Consistently, the combination of EZH2 inhibitor with tamoxifen effectively reduces TNBC progression, suggesting that the RAD51B-EZH2 axis is a potential therapeutic target for TNBC.