目的：探讨微小核糖核酸-133 （miR-133）调控乳腺癌雌激素耐受基因4 （breast cancer anti-estrogen resistance 4, BCAR4）对乳腺癌细胞迁移和侵袭的影响及其机制。 方法： 采集2006年1至12月在郑州大学附属肿瘤医院接受手术切除治疗的80例乳腺癌患者的乳腺癌和相应癌旁组织。RT-PCR检测乳腺癌和癌旁组织BCAR4和miR-133的表达；双荧光素酶检测BCAR4和miR-133之间的关联；划痕实验和Transwell实验分别检测沉默BCAR4或沉默BCAR4和miR-133后乳腺癌MCF-7细胞的迁移和侵袭能力；Western blotting检测Notch1信号通路相关蛋白的表达；裸鼠皮下成瘤实验检测沉默BCAR4对MCF-7细胞成瘤能力的影响；生物统计学分析BCAR4表达和乳腺癌患者临床病理参数及生存率的关系。 结果： 乳腺癌组织中BCAR4表达显著高于癌旁组织（P<0.05）；双荧光素酶实验显示BCAR4可以调控miR-133的表达；沉默BCAR4表达可以抑制乳腺癌MCF-7细胞的迁移和侵袭；沉默miR-133和BCAR4表达的MCF-7细胞的迁移率和穿膜细胞数显著高于仅沉默BCAR4表达的MCF-7细胞[迁移率92.31±8.64）% vs（52.61±5.12）%，P<0.05；穿膜细胞数：(171.38±12.61) vs 8.54±3.29), P<0.01]，抑制miR-133可以逆转BCAR4抑制乳腺癌MCF-7细胞迁移、侵袭能力；沉默BCAR4组裸鼠成瘤的体积和质量都显著减小；沉默BCAR4的MCF-7细胞的Notch1通路相关蛋白表达水平明显下调；BCAR4表达与乳腺癌的病理分期及淋巴结转移显著相关，BCAR4高表达患者生存率较BCAR4低表达患者低。 结论： 乳腺癌MCF-7细胞的侵袭和迁移受到BCAR4和miR-133的双重调控，miR-133可能通过Notch1信号通路调节BCAR4对乳腺癌细胞迁移和侵袭的影响，可为乳腺癌分子靶向治疗及乳腺癌耐药机制的研究提供思路。

Objective: To explore microRNA-133 (miR-133) controling effect of breast cancer anti-estrogen resis- tance 4（BCAR4）gene on migration and invasion of the breast cancer cells as well as its mechanism. Methods:Breast cancer and corresponding paracancerous tissues from the 80 patients with breast cancr who were hospitalized in Tumor Hospital affiliated to Zhengzhou University for surgical resection treatment during January to December 2016 were collected. Expressions of BCAR4 and miR-133 in the breast cancer and paracancerous tissues were de- tected by RT-PCR. A association between BCAR4 and miR-133 was tested by a dual- luciferase assay. Scratch and Transwell assays were respectively used to examine migration and invasion of the breast cancer MCF-7 cell after si-lencing BCAR4 or silencing BCAR4 and miR-133. Expressions of the Notch1 signaling pathway-related proteins were detected by Western blotting assay. A subcutaneous xenograft tumor experiment in nude mice was used to ex-amine effect of silencing BCAR4 on ability of forming tumor of the MCF-7 cell in vivo. Relationships between ex- pression of BCAR4 and clinicopathological parameters as well as survival rate of the patients with breast cancer were analyzed by biostatistics. Results: Expression of BCAR4 in the breast cancer tissue was significantly higher than that in the para-cancer tissue(P<0.05 ). Result of dual-luciferase assay shown that BCAR4 could manage ex- pression of miR-133. Silencing expression of BCAR4 could inhibit migration and invasion of the MCF-7 cell. Mi- gration rate and transmembrane cell number of the MCF-7 cell in which expressions of miR-133 and BCAR4 were silenced were obviously higher than those of the MCF-7 cell in which only expression of BCAR4 was silenced [mi-gration rate: (92.31±8.64)% vs (52.61±5.12)%, P<0.05; transmembrane cell number:(171.38±12.61) vs (28.54±3.29), P<0.01]. Restrain of miR-133 could reverse inhibition of BCAR4 to migration and invasion of the MCF-7 cell. Volumes and wights of the xenograft tumors of the nude mice in which BCAR4 was silenced were significantly decreased. Expressions of Notch1 signaling pathway-related proteins of the MCF-7 cell in which BCAR4 was si- lenced were remarkably down-regulated. Expression of BCAR4 was significantly related to pathological staging and lymph node metastasis of the patients with breast cancer. Survival rate of the patients with high expression of BCAR4 were lower than that of the patients with low expression of BCAR4. Conclusion: Migration and invasion of the breast cancer MCF-7 cell might be doubly managed by BCAR4 and miR-133. miR-133 could targetly regulate effect of BCAR4 on migration and invasion of the breast cancer cell through the Notch1 signaling pathway, which might give some clues for the molecular targeting therapy of breast cancer and the research on drug resistance mech- anism of breast cancer.

河南省基础与前沿技术研究计划基金资助项目（No. 102300410038）