细胞极性蛋白CRB3调控肿瘤干细胞样特性介导乳腺癌他莫昔芬耐药的机制研究

Tamoxifen (TAM) is the preferred endocrine treatment of estrogen receptor-positive breast cancer. TAM resistance, however, has become the biggest obstacle to restricting its application. According to literature, loss of cell polarity is related to cancer stem cell-like properties, and cancer stem cell-like cells may result in TAM resistance. We recently discovered that: 1) absence of cell polarity protein CRB3 in TAM resistance breast cancer cell lines and clinical specimens; 2) loss of CRB3 associated with an increased breast cancer stem cell-like properties; 3) loss of CRB3 activated the Wnt pathways. So we hypothesize that loss of CRB3 may play an important role in the process of TAM resistance of breast cancer, however the specific mechanism is still not clear. Based on the literature and our previous results, we assume that: loss of CRB3 may increase the percentage of breast cancer stem cell-like cells population by activating Wnt pathways, and finally lead to TAM resistance. In this project, We will focus on TAM resistant breast cancer clinical specimens and cell lines to explore the mechanisms of relationship of CRB3 downregulation and TAM resistance in breast cancer by cell and molecular biological and other methods, in order to identify the biomarkers of TAM resistanceand to provide new ideas about TAM resistant in breast cancer.

他莫昔芬（tamoxifen, TAM）是雌激素受体阳性乳腺癌患者内分泌治疗的一线药物，然而TAM耐药却成为阻碍其应用的最大障碍。研究显示：肿瘤干细胞样群落会导致乳腺癌TAM耐药；而细胞极性丢失与肿瘤干细胞样特性密切相关。我们前期研究发现：1) 细胞极性蛋白CRB3在乳腺癌TAM耐药的标本中表达缺失；2) CRB3的降低引起乳腺肿瘤干细胞样群落的增加；3) CRB3的降低导致Wnt通路激活。提示CRB3的缺失在乳腺癌TAM耐药过程中发挥重要作用，但其具体机制不清。故我们设想：CRB3的缺失可能通过激活Wnt通路引起乳腺癌干细胞样群落的增加，从而导致TAM耐药。在本项目中，我们拟利用乳腺癌TAM耐药前后的配对标本，乳腺癌TAM耐药细胞系以及动物模型，应用细胞分子生物学等研究手段，探讨CRB3在TAM耐药中的具体机制。为鉴定TAM耐药的特征生物标志物及治疗新靶点奠定基础。

他莫昔芬（tamoxifen, TAM）是雌激素受体阳性乳腺癌患者内分泌治疗的一线药物，然而TAM耐药却成为阻碍其应用的最大障碍。研究显示：肿瘤干细胞样群落会导致乳腺癌TAM耐药；而细胞极性丢失与肿瘤干细胞样特性密切相关。但其具体机制不清。我们前期的研究结果显示：细胞极性蛋白CRB3在乳腺癌TAM耐药的细胞系及临床标本中表达缺失；并且CRB3的降低会通过激活TAZ/Wnt通路引起乳腺肿瘤干细胞样群落的增加。因此，我们设想：CRB3的缺失可能通过激活Wnt通路引起乳腺癌干细胞样群落的增加，从而导致TAM耐药。本课题在前期研究的基础上，采用了临床乳腺癌标本分析、公共数据库、细胞实验、免疫组化和动物实验等研究发现：1) 细胞极性蛋白CRB3的过表达可以抑制乳腺癌肿瘤干细胞样群落的增加；2) 乳腺癌中CRB3的表达与ER、PR的表达成正相关；3) 乳腺癌中CRB3的降低可能是由于CRB3基因的甲基化引起的；4）细胞极性蛋白CRB3的过表达可以通过激活caspase3途径引起TAM耐药细胞LCC2的凋亡。我们的研究结果为乳腺癌TAM耐药的研究提供了新的思路。受本基金支持，我们以第一作者身份在国际期刊Journal of Celluar and Molecular Medicine、Frontiers in Genetics、Clinical and Experimental Pharmacology and Physiology、Molecular Biology Reports共发表SCI学术论文4篇。本项目的圆满完成为未来深入研究乳腺癌相关治疗策略奠定了良好的基础。