化疗耐受和转移是限制乳腺癌疗效提高的关键原因，EMT有望阐释二者的机制及内在联系。申请者前期建立了呈现EMT表型的乳腺癌耐药细胞株（MCF-7/5-Fu），耐药细胞培养上清能诱导敏感的上皮型乳腺癌细胞发生EMT，筛选发现FGF2活化的Akt/mTOR/EZH2信号可能起重要作用。本项目拟首先应用中和抗体、信号阻断剂及基因干扰技术进一步明确乳腺癌细胞中FGF2对Akt/mTOR/EZH2信号活性的调控及其生物学效应；其次阐述EZH2通过启动子组蛋白甲基化介导FGF2对话miRNAs及其生物学功能；第三将从动物和人体组织水平进一步观察乳腺癌耐药细胞或FGF2介导的信号通路对敏感细胞成瘤能力、化疗敏感性及侵袭转移的影响。本项目的完成将揭示耐药细胞通过分泌FGF2以诱导并维持乳腺癌细胞EMT，将为研究乳腺癌耐药和转移机制及其内在联系提供新思路，并为乳腺癌耐药和转移的早期预防和后期干预提供理论基础。

The chemoresistance and metastasis are the major obstacles for the successful breast cancer treatment clinically. EMT (epithelial-mesenchymal transition) is expected to clarify the mechanisms for chemresistance and metastasis, and the association between them. We have previously established a 5-Fu resistant breast cancer cell line MCF-7/5-Fu with typical EMT features. We found the conditioned culture media from MCF-7/5-Fu cells enabled chemosensitive and epithelial type breast cancer cells to exhibit EMT phenotype, and found FGF2 mediated Akt/mTOR/EZH2 signal activation perhaps played critical role in the EMT induction and maintaince. In the present program, we will first confirm that FGF2 regulates the activation of Akt/mTOR/EZH2 signal and its biological effects in breast cancer cells. Then, we will explore the cross-talk between FGF2 and miRNAs mediated by the histone methylation in the promoter catalyzed by EZH2, and its biological functions. The third, we will investigate the effects of chemoresistant cells or FGF2 mediated signal pathway on the tumorigenicity, chemosensitivity, invasion-metastasis of epithelial type and chemosensitive breast cancer cells in vivo. Through these researches, we will reveal that chemoresistant cells induce and maintain the EMT via secreted FGF2 in breast cancer, which will provide new clues for the mechanisms study for chemoresistance and metastasis and the intrinsic link between them, and a theoretical basis for the prevention and reversion of chemoresistance and metastasis in breast cancer.