PGE2/MFG-E8正反馈环路调控乳腺癌耐药细胞与巨噬细胞交互对话的机制研究

肿瘤微环境中巨噬细胞表型转化影响药物敏感性受到关注，但巨噬细胞与耐药细胞间作用方式、关键调控因子及机制仍未阐明。课题组发现乳腺癌耐药细胞与巨噬细胞间存在相互诱导和促进作用；阿霉素通过促进MCF7/ADR耐药细胞PGE2分泌诱导巨噬细胞M2极化和MFG-E8分泌，而巨噬细胞分泌MFG-E8反馈诱导乳腺癌耐药和PGE2分泌；基于上述基础，申请者创新性提出PGE2/MFG-E8间相互促进、不断循环的正反馈作用可能是耐药细胞与巨噬细胞间互动调控的分子机制。本项目拟通过证实PGE2调控C/EBPβ促进MFG-E8表达诱导巨噬细胞M2极化的分子机制、MFG-E8通过持续激活STAT3/NF-κB/COX-2途径促进PGE2介导乳腺癌细胞耐药性维持，阐明PGE2与MFG-E8相互作用正反馈调控乳腺癌耐药细胞与巨噬细胞交互对话的分子机制，从全新角度为深入探讨肿瘤微环境介导的乳腺癌耐药性奠定理论与实验基础。

The exploration between the drug resistance and the macrophage phenotype change in tumor microenvironment is intensively studied. However, the key regulators and molecular mechanisms are still undefined. In our study, we found that there is a induction and promotion between the breast-resistant cells and macrophage. PGE2 secretion from adriamycin treated-MCF-7/ADR resistant cell promote M2 polarization. Milk fat globule- EGF factor 8 (MFG-E8) secretions is substantially elevated in PGE2-induce M2-like macrophages. In turn, MFG-E8 promotes drug resistance and PGE2 secretion of breast cancer cells. Based on the above work, we propose an innovative notion and idea of that the continuous positive feedback loop between PGE2 and MFG-E8 might be the molecular mechanisms of interaction between resistant cells and macrophages. In this project, to clarify underlying mechanisms of the positive feedback interaction of PGE2 and MFG-E8 regulate the cross talk between breast cancer resistant cells and macrophages, we explored the molecular mechanism of PGE2-induced M2-like macrophages through which the regulation of C/EBPβ binding with MFG-E8 and MFG-E8 promotes the maintain of PGE2-mediated breast cancer cell resistance by sustained activation of STAT3 / NF-κB / COX-2 pathway. This study will lay the foundation of theory and experiment from a new perspective for further research in the tumor microenvironment-mediated drug resistance of breast cancer cells.