极性蛋白DLG5通过调控乳腺癌干细胞样特性参与乳腺癌他莫昔芬耐药的机制研究

Breast cancer is most the common female malignant tumors. Endocrine therapy is a significant choice of ER/PR positive patients in clinical, but endocrine resistance is a tough question. Breast cancer stem cells are one of the key factors for breast cancer endocrine resistance. According to previous reports, the expression of DLG5 is higher than other subtypes in Luminal type of breast cancer. In addition, our previous studies have found that in breast cancer clinical specimens, DLG5 expression was positively correlated with ER/PR status; in TAM resistant specimens and cell lines, the expression of DLG5 showed a significantly decreased. Loss of DLG5 will increase the percentage of breast cancer stem cells characteristics populations, the expression of breast cancer stem cells characteristics factor TAZ and resistant to TAM; but the relationship between DLG5 abnormal expression and TAM resistance of breast cancer is unclear. So we hypothesized that loss of DLG5 expression can enhance breast cancer stem cells characteristics populations by increasing TAZ expression, then leading TAM drug-resistance of breast cancer. We will focus on TAM drug-resistant breast cancer clinical specimens and cell lines, to research the mechanisms of relationship of DLG5 abnormal expression and TAM resistance of breast cancer by nude mice mode. The project completing, will be the first to clarify that DLG5 abnormal expression can regulate the percentage of breast cancer stem cells characteristics populations by influencing TAZ expression, then participate in TAM drug-resistance of breast cancer, and will provide a new way of thinking for clinical TAM resistant treatment.

乳腺癌是女性最常见的恶性肿瘤，内分泌治疗是ER/PR阳性患者的重要选择，但内分泌耐药是影响疗效的棘手问题。乳腺癌干细胞是内分泌耐药的关键因素之一。文献报道细胞极性蛋白DLG5在Luminal型乳腺癌中表达高于其他亚型。申报者前期发现：在临床组织中DLG5表达与ER/PR呈正相关，在他莫昔芬耐药组织与细胞中表达降低；DLG5缺失诱导乳腺癌干细胞样细胞增多、乳腺癌干细胞样标志因子TAZ等增加，对他莫昔芬耐受性增加，但DLG5与他莫昔芬耐药的关系尚不清楚。故设想：DLG5缺失会上调TAZ表达引起乳腺癌干细胞样特性增强，导致乳腺癌他莫昔芬耐药。本研究拟以乳腺癌他莫昔芬耐药标本与细胞株为研究对象，结合动物模型，研究DLG5表达异常与乳腺癌他莫昔芬耐药的具体机制。本项目的完成，将首次阐明DLG5通过调节TAZ表达影响乳腺癌干细胞样特性获得，进而调控乳腺癌他莫昔芬耐药，为临床他莫昔芬耐药治疗提供新思路。

乳腺癌是女性最常见的恶性肿瘤，内分泌治疗是ER/PR阳性患者的重要选择，但内分泌耐药是影响疗效的棘手问题。乳腺癌干细胞是内分泌耐药的关键因素之一。文献报道细胞极性蛋白DLG5在Luminal型乳腺癌中表达高于其他亚型。申报者前期发现：在临床组织中DLG5表达与ER/PR呈正相关，在他莫昔芬耐药组织与细胞中表达降低；DLG5缺失诱导乳腺癌干细胞样细胞增多、乳腺癌干细胞样标志因子TAZ等增加，对他莫昔芬耐受性增加，但DLG5与他莫昔芬耐药的关系尚不清楚。故设想：DLG5缺失会上调TAZ表达引起乳腺癌干细胞样特性增强，导致乳腺癌他莫昔芬耐药。本研究拟以乳腺癌他莫昔芬耐药标本与细胞株为研究对象，结合动物模型，研究DLG5表达异常与乳腺癌他莫昔芬耐药的具体机制。本项目的完成，将首次阐明DLG5通过调节TAZ表达影响乳腺癌干细胞样特性获得，进而调控乳腺癌他莫昔芬耐药，为临床他莫昔芬耐药治疗提供新思路。