Rudraraju Bharath, Droog Marjolein, Abdel-Fatah Tarek M A, Zwart Wilbert, Giannoudis Athina, Malki Mohammed I, Moore David, Patel Hetal, Shaw Jacqui, Ellis Ian O, Chan Steve, Brooke Greg N, Nevedomskaya Ekaterina, Lo Nigro Christiana, Carroll Jason, Coombes R Charles, Bevan Charlotte, Ali Simak, Palmieri Carlo
Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, The Duncan Building, Daulby Street, Liverpool, L69 3GA, UK.
Breast Cancer Res Treat. 2014 Sep;147(2):295-309. doi: 10.1007/s10549-014-3098-0. Epub 2014 Aug 22.
Activating transcription factor-2 (ATF-2) has been implicated as a tumour suppressor in breast cancer (BC). c-JUN N-terminal kinase (JNK) and p38 MAPK phosphorylate ATF-2 within the activation domain (AD), which is required for its transcriptional activity. To date, the role of ATF-2 in determining response to endocrine therapy has not been explored. Effects of ATF-2 loss in the oestrogen receptor (ER)-positive luminal BC cell line MCF7 were explored, as well as its role in response to tamoxifen treatment. Genome-wide chromatin binding patterns of ATF-2 when phosphorylated within the AD in MCF-7 cells were determined using ChIP-seq. The expression of ATF-2 and phosphorylated ATF-2 (pATF-2-Thr71) was determined in a series of 1,650 BC patients and correlated with clinico-pathological features and clinical outcome. Loss of ATF-2 diminished the growth-inhibitory effects of tamoxifen, while tamoxifen treatment induced ATF-2 phosphorylation within the AD, to regulate the expression of a set of 227 genes for proximal phospho-ATF-2 binding, involved in cell development, assembly and survival. Low expression of both ATF-2 and pATF-2-Thr71 was significantly associated with aggressive pathological features. Furthermore, pATF-2 was associated with both p-p38 and pJNK1/2 (< 0.0001). While expression of ATF-2 is not associated with outcome, pATF-2 is associated with longer disease-free (p = 0.002) and BC-specific survival in patients exposed to tamoxifen (p = 0.01). Furthermore, multivariate analysis confirmed pATF-2-Thr71 as an independent prognostic factor. ATF-2 is important for modulating the effect of tamoxifen and phosphorylation of ATF-2 within the AD at Thr71 predicts for improved outcome for ER-positive BC receiving tamoxifen.
活化转录因子2（ATF-2）被认为是乳腺癌（BC）中的一种肿瘤抑制因子。c-JUN氨基末端激酶（JNK）和p38丝裂原活化蛋白激酶（MAPK）在活化域（AD）内使ATF-2磷酸化，这是其转录活性所必需的。迄今为止，尚未探讨ATF-2在决定内分泌治疗反应中的作用。我们研究了ATF-2缺失在雌激素受体（ER）阳性的管腔型BC细胞系MCF7中的影响，以及它在他莫昔芬治疗反应中的作用。使用染色质免疫沉淀测序（ChIP-seq）确定了MCF-7细胞中AD内磷酸化的ATF-2的全基因组染色质结合模式。在1650例BC患者中检测了ATF-2和磷酸化ATF-2（pATF-2-Thr71）的表达，并将其与临床病理特征和临床结局相关联。ATF-2的缺失减弱了他莫昔芬的生长抑制作用，而他莫昔芬治疗诱导AD内ATF-2磷酸化，以调节一组227个基因的表达，这些基因参与细胞发育、组装和存活，且近端有磷酸化ATF-2结合。ATF-2和pATF-2-Thr71的低表达与侵袭性病理特征显著相关。此外，pATF-2与p-p38和pJNK1/2均相关（<0.0001）。虽然ATF-2的表达与结局无关，但pATF-2与接受他莫昔芬治疗患者的更长无病生存期（p = 0.002）和BC特异性生存期相关（p = 0.01）。此外，多变量分析证实pATF-2-Thr71是一个独立的预后因素。ATF-2对于调节他莫昔芬的作用很重要，AD内Thr71位点的ATF-2磷酸化预示着接受他莫昔芬治疗的ER阳性BC患者预后改善。
