多柔比星(DOX)和他莫昔芬(TAM)分别是乳腺癌化疗和内分泌治疗基础成分，大量患者接受治疗时因耐药复发而预后更差。我们前期研究发现lncRNA H19介导乳腺癌细胞DOX和TAM耐药，并通过调控ABCB1或NAT1基因甲基化和表达改变而实现；同时发现H19对此两个基因甲基化和表达改变调控呈双向性。但是，H19特异性、双向性调控ABCB1和NAT1甲基化和表达变化具体机制不明。依据我们的假说，本项目将采用体外转录和RNA-pulldown/蛋白质谱等明确与H19互作的反式作用因子；过表达或敲减等技术阐明H19特异性、双向性调控ABCB1或NAT1甲基化和表达改变具体机制；利用动物实验和临床研究揭示H19表达对DOX和TAM耐药/疗效的影响。本项目将为发现预测DOX或TAM耐药/疗效的新生物标志物、推动个体化乳腺癌化疗或内分泌治疗新方案，开发新治疗药物靶点提供研究基础。

Doxorubicin (DOX) and tamoxifen (TAM) are the basic components of chemotherapy and endocrine therapy for breast cancer, respectively. A large number of patients receiving these therapies encounter recurrence and poor prognosis. In our preliminary study, we found that lncRNA H19 could induce DOX and TAM resistance in the breast cancer cells through regulation of the methylation and expression of ABCB1 and NAT1 genes. More interestingly, the regulation of H19 presented bi-directional effect on these two genes. However, the mechanism of this specific and bi-directional regulation is yet to be explored. Based on our hypothesis, we will first identify the interacting trans-acting factors of H19 through in vitro transcription and RNA-pulldown/protein profiling; then illustrate the mechanism of the specific and bi-directional regulation of H19 on the methylation and expression of ABCA1 and NAT1 using over-expression or knock-down techniques; and finally reveal the effect of H19 expression on DOX and TAM resistance/curative effect from animal models and clinical studies. This work will provide research basis for discovery of new biomarkers for predicting the resistance/efficacy of DOX/TAM, promotion of personalized chemotherapy or endocrine therapy for breast cancer, and development of new drug targets.