Chua Y L, Ito Y, Pole J C M, Newman S, Chin S-F, Stein R C, Ellis I O, Caldas C, O'Hare M J, Murrell A, Edwards P A W
Department of Pathology and Hutchison/Medical Research Council (MRC) Research Centre, University of Cambridge, Cambridge CB2 0XZ, UK.
Oncogene. 2009 Nov 19;28(46):4041-52. doi: 10.1038/onc.2009.259. Epub 2009 Oct 5.
Neuregulin-1 (NRG1) is both a candidate oncogene and a candidate tumour suppressor gene. It not only encodes the heregulins and other mitogenic ligands for the ERBB family, but also causes apoptosis in NRG1-expressing cells. We found that most breast cancer cell lines had reduced or undetectable expression of NRG1. This included cell lines that had translocation breaks in the gene. Similarly, expression in cancers was generally comparable to or less than that in various normal breast samples. Many non-expressing cell lines had extensive methylation of the CpG island at the principal transcription start site at exon 2 of NRG1. Expression was reactivated by demethylation. Many tumours also showed methylation, whereas normal mammary epithelial fragments had none. Lower NRG1 expression correlated with higher methylation. Small interfering RNA (siRNA)-mediated depletion of NRG1 increased net proliferation in a normal breast cell line and a breast cancer cell line that expressed NRG1. The short arm of chromosome 8 is frequently lost in epithelial cancers, and NRG1 is the most centromeric gene that is always affected. NRG1 may therefore be the major tumour suppressor gene postulated to be on 8p: it is in the correct location, is antiproliferative and is silenced in many breast cancers.
神经调节蛋白-1（NRG1）既是一种候选癌基因，也是一种候选肿瘤抑制基因。它不仅编码ERBB家族的神经调节蛋白及其他促有丝分裂配体，还能使表达NRG1的细胞发生凋亡。我们发现，大多数乳腺癌细胞系中NRG1的表达降低或无法检测到。这包括那些在该基因上存在易位断点的细胞系。同样，癌组织中的表达通常与各种正常乳腺样本中的表达相当或更低。许多不表达的细胞系在NRG1第2外显子主要转录起始位点的CpG岛存在广泛甲基化。通过去甲基化可使表达重新激活。许多肿瘤也显示出甲基化，而正常乳腺上皮片段则没有。较低的NRG1表达与较高的甲基化相关。小干扰RNA（siRNA）介导的NRG1缺失增加了一个正常乳腺细胞系和一个表达NRG1的乳腺癌细胞系的净增殖。在上皮癌中，8号染色体短臂经常缺失，而NRG1是总是受影响的最靠近着丝粒的基因。因此，NRG1可能是推测位于8p上的主要肿瘤抑制基因：它处于正确位置，具有抗增殖作用，且在许多乳腺癌中沉默。
