School of Science, The University of Jordan, Amman, Jordan.
School of Medicine, The University of Jordan, Amman, Jordan.
Gene. 2018 Oct 30;675:128-135. doi: 10.1016/j.gene.2018.06.094. Epub 2018 Jun 28.
Triple-negative breast cancer (TNBC) is an aggressive subtype that lacks effective targeted therapeutics strategy and has poor prognosis. Targeting androgen receptor (AR) in TNBC is thought to be a promising approach. We hypothesized that AR, functioning as a transcription factor, controls cell behavior via regulating the expression of microRNA molecules (miRNAs). The expression of 84 breast cancer-specific miRNAs in MDA-MB-231 cells, a highly invasive TNBC model system, was investigated using PCR arrays following treatment of cells with 5α-dihydrotestosterone (DHT). The expression of 33 miRNAs was changed by more than 2 folds including miR-328-3p, which was up-regulated by 13 folds. Transfection of cells with either miR-328-3p mimic or anti-sense molecules decreased cell motility. DHT-mediated effect on the expression and function of CD44, a target of miR-328-3p, was investigated. CD44 expression and cell adhesion to hyaluronic acid (HA) were down-regulated when cells were treated with DHT or transfection with a miR-328-3p mimic. On the other hand, the AR antagonist, bicalutamide, or transfection of cells with miR-328-3p anti-sense molecules had the opposite effect. Cells transfected with miR-328-3p anti-sense molecules reduced the negative effect of DHT on CD44 expression and cell adhesion to HA. In addition, DHT further reduced the expression of CD44 and cell adhesion to HA in cells transfected with miR-328-3p mimic. These results strongly suggest that miRNAs can mediate AR regulation of breast cancer cells and that AR controls the expression of CD44 via miRNA-dependent and independent mechanisms.
三阴性乳腺癌（TNBC）是一种侵袭性亚型，缺乏有效的靶向治疗策略，预后较差。在 TNBC 中靶向雄激素受体（AR）被认为是一种很有前途的方法。我们假设 AR 作为转录因子，通过调节 microRNA 分子（miRNAs）的表达来控制细胞行为。使用 PCR 阵列研究了 MDA-MB-231 细胞（一种高度侵袭性的 TNBC 模型系统）中 84 种乳腺癌特异性 miRNA 的表达，这些细胞在用 5α-二氢睾酮（DHT）处理后。有 33 种 miRNA 的表达发生了超过 2 倍的变化，包括 miR-328-3p，其表达上调了 13 倍。用 miR-328-3p 模拟物或反义分子转染细胞可降低细胞迁移率。研究了 DHT 对 miR-328-3p 靶标 CD44 表达和功能的影响。当用 DHT 处理或转染 miR-328-3p 模拟物时，CD44 表达和细胞与透明质酸（HA）的粘附均下调。另一方面，AR 拮抗剂比卡鲁胺或转染细胞用 miR-328-3p 反义分子具有相反的作用。用 miR-328-3p 反义分子转染的细胞减少了 DHT 对 CD44 表达和细胞与 HA 的粘附的负效应。此外，DHT 进一步降低了转染 miR-328-3p 模拟物的细胞中 CD44 的表达和与 HA 的细胞粘附。这些结果强烈表明，miRNAs 可以介导 AR 对乳腺癌细胞的调节，并且 AR 通过 miRNA 依赖和独立的机制控制 CD44 的表达。
