Department of Neurology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
PLoS Genet. 2010 Jun 10;6(6):e1000979. doi: 10.1371/journal.pgen.1000979.
The function of the tumor suppressor RE1 silencing transcription factor (REST) is lost in colon and small cell lung cancers and is known to induce anchorage-independent growth in human mammary epithelial cells. However, nothing is currently known about the role of this tumor suppressor in breast cancer. Here, we test the hypothesis that loss of REST function plays a role in breast cancer. To assay breast tumors for REST function, we developed a 24-gene signature composed of direct targets of the transcriptional repressor. Using the 24- gene signature, we identified a previously undefined RESTless breast tumor subtype. Using gene set enrichment analysis, we confirmed the aberrant expression of REST target genes in the REST-less tumors, including neuronal gene targets of REST that are normally not expressed outside the nervous system. Examination of REST mRNA identified a truncated splice variant of REST present in the REST-less tumor population, but not other tumors. Histological analysis of 182 outcome-associated breast tumor tissues also identified a subpopulation of tumors that lack full-length, functional REST and over-express the neuroendocrine marker and REST target gene Chromogranin A. Importantly, patients whose tumors were found to be REST-less using either the 24-gene signature or histology had significantly poorer prognosis and were more than twice as likely to undergo disease recurrence within the first 3 years after diagnosis. We show here that REST function is lost in breast cancer, at least in part via an alternative splicing mechanism. Patients with REST-less breast cancer undergo significantly more early disease recurrence than those with fully functional REST, regardless of estrogen receptor or HER2 status. Importantly, REST status may serve as a predictor of poor prognosis, helping to untangle the heterogeneity inherent in disease course and response to treatment. Additionally, the alternative splicing observed in REST-less breast cancer is an attractive therapeutic target.
肿瘤抑制因子 RE1 沉默转录因子（REST）的功能在结肠癌和小细胞肺癌中丧失，已知它能诱导人乳腺上皮细胞的无锚定生长。然而，目前对于这种肿瘤抑制因子在乳腺癌中的作用还一无所知。在这里，我们检验了这样一个假设，即 REST 功能的丧失在乳腺癌中发挥了作用。为了检测乳腺癌中 REST 的功能，我们开发了一个由转录抑制剂的直接靶标组成的 24 基因特征。使用这 24 个基因特征，我们鉴定出了一个以前未定义的 REST 失调型乳腺癌亚型。通过基因集富集分析，我们证实了 REST 无活性肿瘤中 REST 靶基因的异常表达，包括通常不在神经系统外表达的 REST 的神经元靶基因。对 REST mRNA 的检测鉴定出了一种在 REST 失调型肿瘤群体中存在的截断的剪接变异体，但在其他肿瘤中不存在。对 182 份与预后相关的乳腺癌组织的组织学分析也鉴定出了一个缺乏全长、功能性 REST 并过度表达神经内分泌标志物和 REST 靶基因嗜铬粒蛋白 A 的肿瘤亚群。重要的是，使用 24 基因特征或组织学发现肿瘤缺乏全长、功能性 REST 的患者预后明显较差，并且在诊断后 3 年内疾病复发的可能性是其他患者的两倍多。我们在这里表明，REST 功能在乳腺癌中丧失，至少部分是通过一种选择性剪接机制。与具有完整 REST 的患者相比，REST 失调型乳腺癌患者的早期疾病复发率明显更高，而与雌激素受体或 HER2 状态无关。重要的是，REST 状态可作为预后不良的预测因子，有助于理清疾病过程和治疗反应中固有的异质性。此外，在 REST 失调型乳腺癌中观察到的选择性剪接是一个有吸引力的治疗靶点。
