二甲双胍逆转乳腺癌HER2/ER信号交联所致耐药的作用及分子机制

HER2和ER是乳腺癌的两个主要治疗靶点。HER2和ER信号通路间的复杂交联是导致HER2+/ER+乳腺癌内分泌耐药的主要原因。因此，明确该型乳腺癌的耐药机制，寻找有效的干预手段增强内分泌治疗敏感性，是目前研究的热点。我们前期实验发现，传统胰岛素增敏剂二甲双胍可有效抑制HER2+/ER+乳腺癌细胞增殖、逆转耐药性，其可能机制是通过上调miR-17/miR-101来抑制耐药相关分子的表达。生物信息学和荧光素酶报告基因分析证实miR-17/miR-101可直接调控HER2、ER信号交联的枢纽分子AIB1，而AIB1正是介导内分泌耐药的关键分子。我们推测二甲双胍可能通过上调miR-17/miR-101抑制AIB1的表达，从而逆转耐药发生。本研究拟从细胞、动物、临床多个层次研究二甲双胍在HER2+/ER+乳腺癌恶性表型和耐药中的作用及机制，为研究内分泌耐药机制及探索新型治疗策略提供新的思路。

HER2 and ER are two main therapeutic targets of breast cancer. The complex crosstalk between HER2 and ER signal pathways is the leading reason for endocrine resistance of HER2+/ER+ breast cancer. So, for this type of breast cancer, clarifying its endocrine resistance mechanism, searching for effective intervention methods and therapeutic targets is immediate areas of research focus. Our initial studies found that metformin, the traditional insulin sensitizer, could inhibit the proliferation of HER2+/ER+ breast cancer cells and reverse drug resistance, the possible mechanism was up-regulating miR-17/miR-101 and down-regulating molecules relevant to resistance. Bioinformatics and luciferase reporter gene analysis revealed that miR-17/miR-101 could directly regulate AIB1, which is not only the hub molecule associated with HER2/ER signal crosstalk, but also the key molecule related to drug resistance. We hypothesized that metformin might reverse drug resistance phenotype through up-regulating miR-17/miR-101 and down-regulating AIB1. Our study aims to probe the role of metformin in malignant phenotype and drug resistance of HER2+/ER+ breast cancer, to explore its possible mechanism from molecular, cellular, creatural and clinical fields. Our study could afford a new train of thought and theoretical basis for endocrine resistance of breast cancer.