A positive feedback loop: RAD18-YAP-TGF-ß between triple-negative breast cancer and macrophages regulates cancer stemness and progression.

As a key regulator of the DNA translesion synthesis (TLS) pathway, RAD18 is error-prone and contributes to the accumulation of DNA mutations. Our previous study showed that it plays an essential role in the progression of multiple tumors. However, the mechanism through which RAD18 influences triple-negative breast cancer (TNBC), especially the interaction between tumor cells and the tumor microenvironment, remains elusive. In this study, we showed that RAD18 expression is markedly higher in patients with high T stage TNBC and inversely correlated with prognosis. High expression of RAD18 facilitated a highly stem-cell phenotype through the Hippo/YAP pathway, which supports the proliferation of TNBC. In addition, the cytokine byproduct TGF-ß activates macrophages to have an M2-like tumor-associated macrophage (TAM) phenotype. Reciprocally, TGF-ß from TAMs activated RAD18 in TNBC to enhance tumor stemness, forming a positive feedback loop. Inhibition of YAP or TGF-ß breaks this loop and suppresses cancer stemness and proliferation In nude mice, RAD18 promoted subcutaneous transplanted tumor growth and M2-type TAM recruitment. Collectively, the RAD18-YAP-TGF-ß loop is essential for the promotion of the stemness phenotype by TNBC and could be a potential therapeutic target for TNBC.