Division of Molecular Medicine, St. John's Research Institute, Bangalore, India.
Sri Shankara Cancer Hospital and Research Centre, Bangalore, India.
Cancer Med. 2020 Aug;9(15):5587-5597. doi: 10.1002/cam4.3183. Epub 2020 Jun 16.
Despite the established benefits of long-term endocrine therapy, women with hormone receptor-positive breast cancer remain at risk for late relapse. The basis of this is multi-factorial including genetic, epigenetic, and host factors. In this study we have explored the epigenetic regulation of estrogen receptor (ER)-dependent molecular and cellular phenotype by hsa-miR-18a-5p using well-established human ER-positive (ER+) breast cancer cell lines. miR-18a was overexpressed in MCF7 and ZR-75-1 and this led to an increase in the proliferative ability of the cells and concurrently resulted in decreased expression of luminal markers and higher expression of the basal marker, cytokeratin 14. The cells became more migratory with a significant repression of E-cadherin and activation of the Wnt noncanonical pathway. We observed an activation of the planar cell polarity (PCP) pathway with increased activation of JNK pathway and eventually change in actin dynamics. There was increased F-actin polymerization in cells with higher expression of miR-18a. Examination of miR-18a expression in a set of human ER+ breast cancer specimens showed a negative correlation between miR-18a and ESR1 transcripts as well as ER protein. Kaplan-Meier survival analysis of the cohort stratified by tumor hsa-miR-18a-5p levels produced significant differences in disease-free survival (log rank P < .05). This observation was independently validated in the METABRIC cohort. These data provide support for a role of hsa-miR-18a-5p in altering the proliferative and migratory behavior of ER+ cells and its potential utility as a prognostic marker in clinical ER+ breast cancers.
尽管长期内分泌治疗具有明确的益处，但激素受体阳性乳腺癌患者仍存在晚期复发的风险。其基础是多因素的，包括遗传、表观遗传和宿主因素。在这项研究中，我们通过已建立的人雌激素受体阳性（ER+）乳腺癌细胞系，探索了 hsa-miR-18a-5p 对雌激素受体（ER）依赖性分子和细胞表型的表观遗传调控。miR-18a 在 MCF7 和 ZR-75-1 中过表达，导致细胞增殖能力增加，同时腔标志物表达降低，基底标志物细胞角蛋白 14 表达升高。细胞变得更具迁移性，E-钙黏蛋白表达显著下调，Wnt 非经典途径被激活。我们观察到平面细胞极性（PCP）途径的激活，伴随着 JNK 途径的激活和肌动蛋白动力学的变化。miR-18a 表达较高的细胞中 F-肌动蛋白聚合增加。在一组人 ER+乳腺癌标本中检查 miR-18a 的表达，发现 miR-18a 与 ESR1 转录物和 ER 蛋白呈负相关。根据肿瘤 hsa-miR-18a-5p 水平对队列进行分层的 Kaplan-Meier 生存分析显示，无病生存（对数秩 P<.05）有显著差异。这一观察结果在 METABRIC 队列中得到了独立验证。这些数据为 hsa-miR-18a-5p 在改变 ER+细胞的增殖和迁移行为中的作用提供了支持，并且其作为临床 ER+乳腺癌的预后标志物具有潜在的用途。
