雌激素受体ERα调节ABCC家族介导乳腺癌化疗耐药的作用机制研究

Chemotherapy resistance is the main impediment to clinical treatment of cancers. Resistance to chemotherapeutic agents in breast cancer has been increasingly related to the expression of drug-resistant genes, which needs further studies. Both clinical observation and experimental research have shown that ERα plays an important role in drug resistance of breast cancer. ERα as a transcription factor regulates its target genes via either “classical” or “non-classical” ways. High expression of MRPs (the product of ABCC gene family) is greatly responsible for drug resistance by increasing efflux of the cytotoxic drugs from cancer cells and thus lowering intracellular drug concentration. ERα binding sites were detected in the promoter region of ABCC gene using bioinformatics methods, and our previous work found that the ER could bind to the promoter of ABCC1 gene. However, the role of ERα for ABCC family gene is still to be determined. On the basis, we propose that ERα could activate ABCC gene to enhance the resistance of breast cancer by classical or non-classical regulation model. Our study plans to elaborate the molecular mechanism of ER alpha regulation of ABCC family by clinical tissue specimens, related molecular biological techniques and tumor-bearing nude mice, and then improves the treatment strategy of breast cancer.

肿瘤耐药是临床化疗面临的主要难题。乳腺癌细胞耐药与耐药基因异常表达的关系日益彰显，亟待深入研究。临床观察与实验研究均显示，ERα在乳腺癌细胞耐药中扮演重要角色。ERα可通过结合靶基因ERE及 ERE1/2序列以经典和非经典途径调控靶基因表达。ABCC基因家族的高表达是肿瘤细胞耐药的重要机制之一，其基因产物MRPs是一种ATP依赖的膜蛋白，能将底物泵出胞外，使细胞对化疗药物抗性增加。生物信息学分析显示ABCC家族基因启动子区具有ERE及ERE 1/2序列，且前期研究证实ERα能够结合在ABCC1基因启动子区，但ERα调节ABCC基因家族的机制不明。本项目假设：ERα能通过经典或非经典途径促进ABCC基因表达从而提高乳腺癌对药物的抗性，化疗同时拮抗MRPs蛋白作用可提高ER阳性乳腺癌化疗敏感性。项目拟从临床标本、分子细胞、动物模型层面，阐述ERα调控ABCC家族的分子机制，完善乳腺癌治疗方案。

乳腺癌是女性最常见的激素依赖性恶性肿瘤之一。雌激素受体（ER）在乳腺癌患者中的阳性率为60%-70%。ER阳性（ER+）乳腺癌患者在内分泌治疗无效后，往往接受化疗治疗，此外临床资料显示ER+乳腺癌患者对一线化疗药物更加耐受。本研究旨在探讨ER +乳腺癌的化疗耐药机制及提出潜在的治疗靶点。已有研究表明，ERα的表达能够逆转化疗药物诱导的乳腺癌细胞凋亡，我们前期结果也发现ERα能够上调多药耐药基因的表达从而增强乳腺癌对化疗药物抗药性。以上数据提示，ERα在乳腺癌化疗耐药中起着重要作用。.耐药基因ABCC家族基因编码的多药耐药相关蛋白（multi-drug resistance proteins，MRPs），它能利用ATP能量将细胞内的底物泵出细胞外，使得肿瘤细胞内药物的绝对浓度降低，从而增加肿瘤细胞对药物的抗性，其表达量增加是肿瘤细胞多药耐药（multidrug resistance，MDR）的主要机制之一。本研究证实，在ER＋的乳腺癌细胞耐药过程中ERα与转录因子Sp1形成蛋白复合物，进而结合在ABCC1及ABCC4基因的启动子区，正向调控两个基因的转录，从而提高乳腺癌对药物的抗性，化疗同时拮抗ERα蛋白作用可以提高ER阳性乳腺癌化疗敏感性。本课题的实施对完善ER+乳腺癌的治疗方案，提高ER+乳腺癌化疗效果有重要的理论意义。