他莫昔芬（TAM）是治疗雌激素受体阳性（ER+）乳腺癌患者的主要方式，而TAM耐药是导致内分泌治疗失败的原因，因此对其产生机制及逆转措施的研究具有极重要意义。我们研究发现AFF3在TAM耐药细胞株和患者体内高表达，AFF3过表达可产生耐TAM功能，但具体诱导耐药机制不明；预实验提示：AFF3可促进自噬，也可上调Atg12表达，而Atg12是自噬关键基因之一；还发现miR-138-5p可下调AFF3表达。在以上研究基础之上我们提出假设： miR-138-5p/AFF3/Atg12通路可调节乳腺癌细胞自噬活性，从而调控TAM耐药性。本项目将通过体内外实验，深入探讨miR-138-5p/AFF3/Atg12通路在乳腺癌TAM耐药中的生物学功能及具体的分子机制，并结合临床病例资料分析该通路及自噬通路与TAM耐药的相关性，为乳腺癌TAM耐药患者提供新的预测指标及治疗靶点。

Tamoxifen (TAM) is the main method for the treatment of estrogen receptor-positive (ER+) breast cancer patients, and TAM resistance is the cause of the failure of endocrine therapy. Thus the study of its mechanism and reversal measures is of great significance. Our study found that AFF3 is highly expressed in TAM-resistant cell lines and breast cancer patients. AFF3 overexpression can produce TAM-resistance, but the specific mechanism of induction of drug resistance is unknown. Pre-experiment suggests that AFF3 can promote autophagy and up-regulate the expression of Atg12, which is one of the key genes of autophagy. And miR-138-5p was also found to down-regulate AFF3 expression. Based on the above studies, we hypothesized that the miR-138-5p/AFF3/Atg12 axis regulates autophagy activity in breast cancer cells and regulates TAM resistance. This project will explore the biological function and specific molecular mechanism of miR-138-5p/AFF3/Atg12 axis in TAM resistance of breast cancer through in vitro and in vivo experiments, and analyze this pathway and autophagy pathway with clinical case data. The relevance of TAM resistance provides new predictive indicators and therapeutic targets for TAM-resistant patients with breast cancer.