临床发现乳腺癌化疗耐药与肿瘤远处转移显著相关，巨噬细胞（Mф）在化疗耐药肿瘤中介导癌细胞转移报导甚少，且机制尚未阐明。本项目前期发现，乳腺癌耐药细胞激活Mф中MAPK4/NCOA3诱导其朝M2极化，最后表明耐药癌细胞诱导的M2型Mф促进了乳腺癌细胞转移。在本课题研究中，我们拟从四个部分阐明化疗耐药乳腺癌细胞激活NCOA3促进Mф朝M2型极化诱导癌细胞转移的作用与机制：1）乳腺癌耐药细胞激活Mф中MAPK4诱导其M2极化作用与机制；2）MAPK4磷酸化NCOA3抑制其降解并促进其入核，进而促进Mф朝M2极化作用与机制；3）NCOA3入核调控基因转录促进Mф朝M2极化机制；4）MAPK4/NCOA3通过诱导Mф朝M2极化促进乳腺癌转移作用与机制。本课题将为化疗耐药乳腺癌细胞转移的机制提供新理论，为转移乳腺癌提供潜在的诊断标志物及药物治疗靶点。

Metastasis and chemoresistance in breast cancer are linked phenomena, however the molecular basis for this link is unknown. There are few reports that chemoresistant cancer cells activate macrophages (Mф) to promote tumor metastasis. Our preliminary experiments showed that chemoresistant breast cancer cells can induce Mф to polarize towards M2 type by enhancing the MAPK4/NCOA3 activity in Mф. Moverover, we showed that the M2 Mф induced by the chemoresistant cancer cells promoted breast cancer cell migration. In this project, we will uncover the roles and mechanisms that chemoresistant cancer cells activate NCOA3 to promote Mф to M2 polarization, and M2 Mф induces cancer cells migration: 1) the roles and mechanisms that chemoresistant breast cancer cells activate MAPK4 of Mф and induce M2 polarization; 2) the roles and mechanisms that MAPK4 phosphorylates NCOA3 in Mф to inhibit the degradation of NCOA3 and promotes nucleus entry of NCOA3, and thereby promoting Mф to M2 polarization; 3) the mechanisms that NCOA3 promotes Mф to M2 polarization by inducing transcription of some genes associated with M2 polarization; 4) the roles and mechanisms that MAPK4/NCOA3 promotes breast cancer metastasis by inducing Mф to M2 polarization. This project will provide a new theory for tumor metastasis in chemoresistant breast cancer, and provide potential diagnostic markers and therapeutic targets for metastatic breast cancer.