Noyan Senem, Gür Dedeoğlu Bala
Biotechnology Institute, Ankara University, Ankara, Türkiye.
Balkan Med J. 2025 Mar 3;42(2):150-156. doi: 10.4274/balkanmedj.galenos.2025.2024-12-47.
Endocrine resistance remains a significant therapeutic challenge in estrogen receptor-positive (ER+) breast cancer, the most common subtype, contributing to increased morbidity and mortality. The interaction between ER and HER family receptors, particularly HER2 and epidermal growth factor receptor (EGFR), drives resistance to standard therapies such as tamoxifen and trastuzumab by activating key signaling pathways, including PI3K/AKT and RAS/MAPK. Dysregulated miRNAs, which are non-coding gene expression regulators, have been linked to therapy response.
To investigate the role of miR-99b-5p in ER-HER2/EGFR crosstalk in BT-474 cells.
Experimental study.
The expression profile and prognostic significance of miR- 99b-5p in breast cancer were analyzed using The Cancer Genome Atlas (TCGA) database. BT-474 cells were transfected with miR-99b-5p mimics and inhibitors, followed by treatment with tamoxifen and trastuzumab to assess their impact on cell proliferation and ER-HER2/EGFR crosstalk. Western blotting was performed to quantify EGFR, HER2, and ESR1 protein levels. Real-time proliferation analysis evaluated changes in cell growth following miRNA transfection and drug treatment.
The study revealed that miR-99b-5p is significantly overexpressed in tumors compared to normal tissues and is associated with poor patient survival and enhanced ER signaling. Transfection with miR-99b-5p mimics increased ESR1 expression and cell proliferation, even in the presence of tamoxifen or trastuzumab, indicating that miR-99b-5p contributes to therapy resistance through receptor crosstalk. Conversely, miR-99b-5p inhibition significantly restored drug sensitivity, reducing proliferation and enhancing the effectiveness of tamoxifen and trastuzumab.
These findings establish miR-99b-5p as a key regulator of endocrine and HER2-targeted therapy resistance. Targeting miR-99b-5p could represent a potential therapeutic strategy to improve treatment outcomes in ER+/HER2+ breast cancer. Further research is needed to clarify the underlying molecular mechanisms and validate the therapeutic potential of miR-99b-5p inhibition in clinical applications.
内分泌抵抗仍然是雌激素受体阳性（ER+）乳腺癌这一最常见亚型中的重大治疗挑战，会导致发病率和死亡率上升。ER与HER家族受体，特别是HER2和表皮生长因子受体（EGFR）之间的相互作用，通过激活关键信号通路（包括PI3K/AKT和RAS/MAPK），导致对他莫昔芬和曲妥珠单抗等标准疗法产生耐药性。失调的微小RNA（miRNA）作为非编码基因表达调节因子，与治疗反应有关。
研究miR-99b-5p在BT-474细胞中ER-HER2/EGFR相互作用中的作用。
实验性研究。
使用癌症基因组图谱（TCGA）数据库分析miR-99b-5p在乳腺癌中的表达谱及预后意义。用miR-99b-5p模拟物和抑制剂转染BT-474细胞，随后用他莫昔芬和曲妥珠单抗处理，以评估它们对细胞增殖和ER-HER2/EGFR相互作用的影响。进行蛋白质免疫印迹法以定量EGFR、HER2和ESR1蛋白水平。实时增殖分析评估miRNA转染和药物处理后细胞生长的变化。
研究表明，与正常组织相比，miR-99b-5p在肿瘤中显著过表达，且与患者生存率低和ER信号增强有关。用miR-99b-5p模拟物转染可增加ESR1表达和细胞增殖，即使在存在他莫昔芬或曲妥珠单抗的情况下也是如此，这表明miR-99b-5p通过受体相互作用导致治疗耐药。相反，抑制miR-99b-5p可显著恢复药物敏感性，减少增殖并增强他莫昔芬和曲妥珠单抗的疗效。
这些发现确立了miR-99b-5p作为内分泌和HER2靶向治疗耐药的关键调节因子。靶向miR-99b-5p可能代表一种潜在的治疗策略，以改善ER+/HER2+乳腺癌的治疗效果。需要进一步研究以阐明潜在的分子机制，并在临床应用中验证抑制miR-99b-5p的治疗潜力。
