Noyan Senem
Biotechnology Institute, Ankara University, Ankara, 06560, Turkey.
Mol Biol Rep. 2025 May 23;52(1):496. doi: 10.1007/s11033-025-10598-w.
Cancer cells employ various adaptive mechanisms to withstand stressors, with one notable pathway being the unfolded protein response (UPR), crucial in fostering endocrine resistance within ER-positive breast cancer. Investigating miRNAs within tumors holds promise for identifying key miRNA-gene interactions pivotal for tumor characteristics like proliferation and resistance to treatment. Notably, XBP1 emerges as a pivotal player in UPR within the endoplasmic reticulum, particularly through the inositol-requiring enzyme 1 (IRE1α) - the X-box-binding protein 1 (XBP1) pathway, presenting a compelling target for clinical intervention. In this study, I explore the regulatory role of miR-770-5p in modulating XBP1 expression and its potential as a therapeutic target in luminal breast cancer.
The role of XBP1 in cancer cell pathogenesis has been investigated using bioinformatics tools to analyze its expression in breast cancer samples and its association with clinical outcomes. The relationship between miR-770-5p and XBP1 was further explored through bioinformatics analysis and ROC plot assessment. qRT-PCR and bioinformatics data confirmed the negative correlation between miR-770-5p and XBP1, particularly in Luminal A subtype with wild-type p53. My results demonstrated that miR-770-5p targets XBP1, inhibiting its spliced form and reducing its downstream transcriptional activity. Moreover, I found that miR-770-5p can modulate tamoxifen sensitivity by influencing the XBP1/ESR1 axis in breast cancer cells. Overexpression of miR-770-5p led to decreased ESR1 levels, enhancing tamoxifen efficacy and suggesting a potential novel therapeutic approach for luminal subtype breast cancer.
miR-770-5p has a growth-inhibitory function in luminal breast cancer, where its suppression of XBP1 contributes to the increased sensitivity to tamoxifen.
癌细胞采用多种适应性机制来抵御应激源，其中一条显著途径是未折叠蛋白反应（UPR），这在雌激素受体阳性乳腺癌中促进内分泌抵抗方面至关重要。研究肿瘤内的微小RNA（miRNA）有望识别对于肿瘤增殖和治疗耐药性等特征至关重要的关键miRNA-基因相互作用。值得注意的是，X盒结合蛋白1（XBP1）在内质网的UPR中成为关键角色，特别是通过肌醇需求酶1（IRE1α）-XBP1途径，这为临床干预提供了一个有吸引力的靶点。在本研究中，我探讨了miR-770-5p在调节XBP1表达中的调控作用及其作为腔面型乳腺癌治疗靶点的潜力。
利用生物信息学工具研究了XBP1在癌细胞发病机制中的作用，分析其在乳腺癌样本中的表达及其与临床结果的关联。通过生物信息学分析和ROC曲线评估进一步探究了miR-770-5p与XBP1之间的关系。定量逆转录聚合酶链反应（qRT-PCR）和生物信息学数据证实了miR-770-5p与XBP1之间的负相关，特别是在具有野生型p53的腔面A型亚型中。我的结果表明，miR-770-5p靶向XBP1，抑制其剪接形式并降低其下游转录活性。此外，我发现miR-770-5p可通过影响乳腺癌细胞中的XBP1/雌激素受体α（ESR1）轴来调节他莫昔芬敏感性。miR-770-5p的过表达导致ESR1水平降低，增强了他莫昔芬的疗效，并提示了一种针对腔面型亚型乳腺癌的潜在新治疗方法。
miR-770-5p在腔面型乳腺癌中具有生长抑制功能，其对XBP1的抑制作用有助于提高对他莫昔芬的敏感性。
