Circular RNA circWWC3 augments breast cancer progression through promoting M2 macrophage polarization and tumor immune escape via regulating the expression and secretion of IL-4

Interaction between tumor cells and tumor microenvironment (TME) is critical to promote tumor progression and metastasis. As the most abundant immune cells in TME, macrophages can be polarized into M2-like tumor-associated macrophages (TAMs) which further promote tumor progression. However, to date, the molecular mechanisms of TAM polarization in TME are still largely unknown. In the present study, we revealed that circular RNA circWWC3 could up-regulate the expression and secretion of IL-4 in breast cancer cells. Enhanced secretion of IL-4 from breast cancer cells could augment the M2-like polarization of macrophages in TME, which further promotes the migration of breast cancer cells. In addition, increased secretion of IL-4 from breast cancer cells could induce the expression PD-L1 in M2 macrophages. Moreover, up-regulated IL-4 also enhanced the expression of PD-L1 in breast cancer cells, which further facilitates breast cancer immune evasion. Though analyzing the expression of circWWC3, IL-4, PD-L1, and CD163 in 140 cases of breast cancer tissues, we found that high expression of circWWC3 was associated with poor overall survival and disease-free survival of breast cancer patients. Breast cancer patients with circWWC3^high/PD-L1^high breast cancer cells and CD163^high macrophages had a poorer overall survival and disease-free survival. Conclusively, circWWC3 might augment breast cancer progression through promoting M2 macrophage polarization and tumor immune escape via regulating the expression and secretion of IL-4. CircWWC3 might be a potential therapeutic target in breast cancer.