Department of Biochemistry and Molecular Biology, Wright State University School of Medicine, 3640 Colonel Glenn Highway, Dayton, OH, 45435, USA.
Cancer Metastasis Rev. 2018 Sep;37(2-3):491-507. doi: 10.1007/s10555-018-9753-x.
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is difficult to treat since cells lack the three receptors (ES, PR, or HER) that the most effective treatments target. We have used a well-established TNBC cell line (MDA-MB-231) from which we found evidence in support for a phospholipase D (PLD)-mediated tumor growth and metastasis: high levels of expression of PLD, as well as the absence of inhibitory miRs (such as miR-203) and 3'-mRNA PARN deadenylase activity in these cells. Such findings are not present in a luminal B cell line, MCF-7, and we propose a new miR•PARN•PLD node that is not uniform across breast cancer molecular subtypes and as such TNBC could be pharmacologically targeted differentially. We review the participation of PLD and phosphatidic acid (PA), its enzymatic product, as new "players" in breast cancer biology, with the aspects of regulation of the tumor microenvironment, macrophage polarization, regulation of PLD transcripts by specific miRs and deadenylases, and PLD-regulated exosome biogenesis. A new signaling miR•PARN•PLD node could serve as new biomarkers for TNBC abnormal signaling and metastatic disease staging, potentially before metastases are able to be visualized using conventional imaging.
三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌亚型，由于细胞缺乏最有效治疗方法针对的三种受体（雌激素受体、孕激素受体或人表皮生长因子受体 2），因此难以治疗。我们使用了一种成熟的 TNBC 细胞系（MDA-MB-231），从中我们发现了支持磷脂酶 D（PLD）介导的肿瘤生长和转移的证据：PLD 表达水平高，以及这些细胞中抑制性 miR（如 miR-203）和 3'-mRNA PARN 脱腺苷酸酶活性缺失。在 luminal B 细胞系 MCF-7 中不存在这些发现，我们提出了一个新的 miR•PARN•PLD 节点，它在乳腺癌分子亚型中并不统一，因此 TNBC 可以在药理学上进行差异化靶向治疗。我们回顾了 PLD 和其酶产物磷脂酸（PA）作为乳腺癌生物学中的新“参与者”的参与，包括肿瘤微环境的调节、巨噬细胞极化、特定 miR 和脱腺苷酸酶对 PLD 转录物的调节以及 PLD 调节的外泌体发生。新的信号 miR•PARN•PLD 节点可以作为 TNBC 异常信号和转移性疾病分期的新生物标志物，潜在地在使用常规成像能够检测到转移之前。
