MIR4435-2HG promotes breast cancer evolution through miR-205-5p/UBE2N axis and exosome-mediated macrophage M2-like polarization.

The lncRNA/microRNA/mRNA competing endogenous RNA (ceRNA) network has been implicated in the progression of various cancers. However, its role in breast cancer prognosis remains largely unexplored. Exosomes, as mediators of intercellular communication, regulate tumor-associated macrophages (TAMs) polarization by transferring biomolecules. The mechanism by which exosomal MIR4435-2HG diverted from breast cancer cell modulates TAMs polarization, however, has not been fully elucidated. Here, we demonstrate that overexpression of MIR4435-2HG in breast cancer correlates with poor patient prognosis. Functionally, MIR4435-2HG enhances breast cancer cell proliferation, migration, invasion, angiogenesis, and epithelial-mesenchymal transition (EMT) in vitro while driving tumor growth and metastasis in vivo. Mechanistically, MIR4435-2HG as a ceRNA inhibits the degradation of target gene UBE2N by absorbing miR-205-5p. This ceRNA network facilitates breast cancer progression by activating the Wnt/β-catenin signaling pathway. Furthermore, breast cancer cell-derived exosomes deliver MIR4435-2HG to TAMs, promoting M2 polarization through C/EBPβ activation, which further exacerbates cancer progression. Collectively, our findings unveil a novel MIR4435-2HG/miR-205-5p/UBE2N ceRNA network that drives breast cancer progression and highlights exosomal MIR4435-2HG as a critical mediator of TAM polarization, offering potential as a potential biomarker and therapeutic target for breast cancer.