Background/Objectives: Estrogen receptor-α coactivator MED1 is overexpressed in 40–60% of human breast cancers, and its high expression correlates with poor disease-free survival of patients undergoing anti-estrogen therapy. However, the molecular mechanism underlying MED1 upregulation and activation in breast cancer treatment resistance remains elusive.Methods: miRNA and mRNA expression analysis was performed using the NCBI GEO database. MED1 targeting and its impact on therapy resistance was evaluated in control and tamoxifen-resistant breast cancer cell lines by miR-205 overexpression and inhibition. Immunoblotting, chromatin immunoprecipitation, and luciferase reporter assays were used to understand the molecular mechanism of MED1-mediated tamoxifen resistance. Mice xenograft models were used to validate treatment efficacy and molecular mechanisms in vivo.Results: miR-205 was found to directly target and suppress the expression of MED1 through bioinformatic analyses and experimental validations. An inverse correlation of miR-205 and MED1 was observed in breast cancer patients with high MED1/low miR-205, indicative of poor prognosis in long-term anti-estrogen treatment. Furthermore, the depletion of miR-205 was observed in tamoxifen-resistant breast cancer cells overexpressing MED1. The restoration of miR-205 expression attenuated MED1 expression and re-sensitized cells to tamoxifen both in vitro and in vivo. Interestingly, miR205 was also found to target another key regulatory gene, HER3, which drives PI3K/Akt signaling and MED1 activation by phosphorylation. Importantly, we found ER target gene transcription and promoter cofactor recruitment by tamoxifen can be reversed by induced miR205 expression.Conclusions: Altogether, miR-205 functions as a negative regulator of MED1 and HER3, affecting the regulation of the HER3-PI3K/Akt-MED1 axis in anti-estrogen resistance, and could serve as a potential therapeutic regime to overcome treatment resistance.
背景/目的：雌激素受体α共激活因子MED1在40-60%的人类乳腺癌中过表达，其高表达与接受抗雌激素治疗患者较差的无病生存期相关。然而，MED1在乳腺癌治疗耐药中的上调及激活机制尚不明确。 方法：通过NCBI GEO数据库进行miRNA与mRNA表达谱分析。在对照组和他莫昔芬耐药乳腺癌细胞系中，通过过表达及抑制miR-205评估其对MED1的靶向调控作用及对治疗耐药的影响。采用免疫印迹、染色质免疫共沉淀及荧光素酶报告基因实验解析MED1介导他莫昔芬耐药的分子机制，并利用小鼠移植瘤模型在体内验证治疗效果及分子机制。 结果：生物信息学分析与实验验证表明，miR-205可直接靶向抑制MED1表达。在MED1高表达/miR-205低表达的乳腺癌患者中观察到两者呈负相关，提示长期抗雌激素治疗预后不良。此外，在他莫昔芬耐药且MED1过表达的乳腺癌细胞中检测到miR-205表达缺失。恢复miR-205表达可降低MED1水平，并在体外和体内实验中使细胞重新对他莫昔芬敏感。值得注意的是，miR-205还能靶向调控另一关键基因HER3，该基因通过激活PI3K/Akt信号通路介导MED1磷酸化激活。重要的是，研究发现他莫昔芬诱导的ER靶基因转录及启动子共因子募集可被miR-205表达所逆转。 结论：miR-205作为MED1与HER3的负向调控因子，通过调控HER3-PI3K/Akt-MED1信号轴影响抗雌激素治疗耐药，可能成为克服治疗耐药的潜在治疗策略。
肿瘤(癌症)患者之家