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

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。

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.