miRNA传统上在细胞浆中通过结合靶基因3’UTR抑制翻译或降解mRNA进而发挥负向调控作用，这很难解释许多定位于细胞核内miRNA作用机制。肿瘤相关miRNA低表达是肿瘤细胞重要分子特征，而低表达miRNA如何精准调控肿瘤生物学行为仍面临诸多挑战。我们前期研究工作发现定位于细胞核内miRNA与公认的miRNA在胞浆中负向调控机制不同，可通过结合增强子序列进而发挥基因转录激活作用，命名为NamiRNA （Nuclear Activating miRNA）。本项目以乳腺癌低表达miRNA与潜在靶基因为研究对象，确定乳腺癌中低表达miR-339改变增强子活性与GPER1正向调控关系，力图阐明miR-339对GPER1正向调控分子机制，探讨miR-339对GPER1正向调控对乳腺癌细胞生物学行为影响，从全新角度诠释肿瘤相关miRNA在乳腺癌发生发展中的作用，寻找miRNA干预对乳腺癌治疗新策略。

MicroRNAs (miRNAs) are small non-coding RNAs that canonically inhibit the translation or promote degradation messenger RNAs (mRNAs) through an RNA-RNA interaction with the 3-untranslated region (UTR) of target genes in the cytoplasm. However, the function of abundant miRNAs in the nucleus remained unclear. Notably, it was found that miRNAs tend to have a lower expression in cancer, which is acknowledged as an important molecular characteristic of cancer cells. Yet many challenges remain to illustrate the mechanisms how biologic behavior of tumors is properly controlled by such low expression miRNAs. In our previous research, we found that the function of nuclear miRNAs is completely different from cytoplasmic miRNAs. In contrast to the negative regulation, the nuclear miRNAs could activate gene transcription by binding to enhancer regions, termed as NamiRNA (Nuclear Activating miRNA). Here, our current proposed project try to explore positive regulation of low expression miRNAs in breast cancer and focus on investigating the function of miR-339 in the regulation of enhancer activities and expression of GPER1. We will illuminate the mechanisms through which GPER1 gene expression is up regulated by miR-339, and further explore the function of miR-339 and GPER1 throughout each stage of breast cancer. In the end, we hope to uncover a new perspective towards understanding the function of tumor associated miRNAs in breast cancer development, and provide a new and effective strategy to inhibit breast cancer development through NamiRNA intervention.