CAF源性外泌体递送LncRNA-TRA介导乳腺癌三苯氧胺耐药的机制研究

癌相关成纤维细胞（CAF）与乳腺癌三苯氧胺耐药相关。预实验发现CAF源性外泌体降低乳腺癌细胞对三苯氧胺的敏感性；已筛选获得与其耐药相关的关键新型LncRNA-TRA，在CAF和外泌体中均高表达；CAF外泌体处理可增加乳腺癌细胞LncRNA-TRA的表达，并降低三苯氧胺治疗的敏感性。鉴此，本项目关注的科学问题是：CAF源性外泌体递送LncRNA-TRA介导乳腺癌三苯氧胺耐药的机制。项目研究拟明确CAF外泌体递送LncRNA-TRA诱导三苯氧胺耐药的作用；阐明LncRNA-TRA结合FOXP3位点及作用方式；解析LncRNA-TRA/FOXP3调控APC及其下游Wnt/β-catenin通路激活介导耐药的分子机制，并发现关键调控分子。藉此，明晰CAF源性外泌体递送LncRNA-TRA推动细胞周期介导三苯氧胺耐药的机制，探索形成以靶向CAF及其外泌体LncRNA-TRA为核心的内分泌治疗新策略。

Cancer-associated fibroblasts (CAF) was associated with tamoxifen resistance in breast cancer. Our previous study found that CAF-derived exosomes can decrease tamoxifen treatment sensitivity in breast cancer cell lines. In addition, novel LncRNA-TRA was screened and selected as a key LncRNA to be associated with tamoxifen resistance, which was highly expressed in both CAF cells and their exosomes. Moreover, CAF-derived exosomes could upregulate LncRNA-TRA expression in breast cancer cells, thus decreasing tamoxifen treatment sensitivity. On this basis, scientific problems of this program would mainly focus on the mechanisms of how CAF-derived exosomes to transfer LncRNA-TRA to mediate tamoxifen resistance. This study would plan to confirm the role of CAF-derived LncRNA-TRA in inducing tamoxifen resistance, elucidating FOXP3 binding site of LncRNA-TRA and its functional type, analyzing the molecular mechanism of LncRNA-TRA/FOXP3 in regulating APC and its downstream Wnt/β-catenin pathway activation to induce tamoxifen resistance, and finding key regulator factors. Thereby, we will elucidate the mechanism that transfer of CAF-derived LncRNA-TRA vis exosomes would induce tamoxifen resistance by promoting cell cycle progression, and further investigating and forming a new strategy of endocrine therapy by targeting CAF and its exosomal LncRNA-TRA in breast cancer.