β-arrestin2与β-catenin作用调控Wnt/β-catenin通路影响乳腺癌多药耐药

Multidrug resistance (MDR) becomes the major obstacle in the treatment of breast cancer. The human multidrug resistance 1 gene (MDR1) encodes the membrane-located efflux pump P-glycoprotein (P-gp)，which is a key target in reversing multidrug resistance of breast cancer. .Our team found that the expression of β-arrestin2 was closely related to MDR1 in breast cancer cells. Otherwise, overexpression or silence of β-arrestin2 had effects on MDR. As we known, MDR1 is a direct target gene regulated by Wnt/β-catenin signaling pathway, in which β-arrestin2 acts necessarily. .Then we found β-arrestin2 binding with β-catenin in the nuclear of multidrug resistant breast cancer cell by co-IP, which really draws our attention. Whether β-arrestin2 interacting with β-catenin regulates the transcription of specific target genes by binding with their promoters? This study aims to investigate our hypothesis, find key target genes and proteins regulated by β -arrestin2/ β -catenin, more important, define the specific mechanism in order to identify β -arrestin2 as a new molecular target for reversing malignant transformation of breast cancer.

多药耐药是导致乳腺癌化疗失败的重要原因，MDR1基因编码的P-糖蛋白（MDR1/P-gp）是逆转乳腺癌多药耐药最重要的靶点。课题组发现乳腺癌细胞中β-arrestin2与MDR1的表达密切相关。MDR1基因是Wnt/β-catenin 通路的直接靶基因，β-arrestin2是该通路的必需作用因子，提示β-arrestin2通过Wnt/β-catenin 通路影响MDR1的表达及乳腺癌多药耐药。随后我们发现在耐药细胞胞核中β-arrestin2与β-catenin结合，推测二者相互作用结合至特定靶基因的启动子区并激活转录。本课题拟在前期实验基础上，明确β-arrestin2/β-catenin相互作用对Wnt/β-catenin通路的影响，寻找关键性靶基因和靶蛋白，为β-arrestin2作为遏制乳腺癌恶行性的新靶点提供理论支持和实验依据。