ERRγ target genes are poor prognostic factors in Tamoxifen-treated breast cancer.
ERRγ target genes are poor prognostic factors in Tamoxifen-treated breast cancer.
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DOI：
10.1186/s13046-015-0150-9
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发表时间：
2015-05-15
期刊：
影响因子：
--
通讯作者：
Riggins RB
中科院分区：
文献类型：
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作者：
Madhavan S;Gusev Y;Singh S;Riggins RB
用三苯氧胺()治疗的雌激素(ER+)和/或孕激素受体阳性(PGR+)乳腺肿瘤中，有三分之一对初始治疗没有反应，其余70%有未来复发的风险。雌激素相关受体γ(ESRRG，ERRγ)是一种孤儿核受体，与经典ER具有广泛的结构相似性，广泛参与能量稳态的转录调控。我们以前已经在ER+乳腺癌模型中证明了ERRγ诱导对耐药，并且该受体的转录活性是通过激活ERK/MAPK通路而改变的。我们假设ERRγ的过度激活或过度表达诱导了一种促进生存的转录程序，从而削弱了抑制ER+乳腺癌生长的能力。本研究的目的是确定ERRγ靶基因是否与治疗ER+乳腺癌的无远处转移生存期(DMF)减少有关。原始基因表达数据来自3项公开的乳腺癌临床研究，这些研究涉及接受作为唯一内分泌治疗的ER+乳腺癌患者。ERRγ靶基因选自两项研究，这些研究发表了对ERRγ启动子占有率的染色质免疫沉淀(ChIP)分析。用Kaplan-Meier估计确定ERRγ靶基因与DMF的相关性，并在表达外源性ERRγ的ER+、MCF7乳腺癌细胞中验证所选基因。在5年内经历过糖尿病的女性中，37个有效的受体靶基因在统计上显著改变，并可以将几项独立研究归类为较差的DMF和良好的DMF。两个基因(EEF1A2和PPIF)同样可以用DMFS分离ER+、处理的乳腺肿瘤，并在含有外源性ERRγ的ER+乳腺癌细胞模型中检测它们的蛋白水平。最后，ERK/MAPK高激活的ER+乳腺癌模型中ERRγ和这两个靶基因的表达增加。在ER+、治疗的乳腺癌中，ERRγ信号与DMF差相关，ESRRG、EEF1A2和PPIF组成一个3基因信号节点，可能通过激活ERK/MAPK通路参与耐药。
One-third of estrogen (ER+) and/or progesterone receptor-positive (PGR+) breast tumors treated with Tamoxifen (TAM) do not respond to initial treatment, and the remaining 70% are at risk to relapse in the future. Estrogen-related receptor gamma (ESRRG, ERRγ) is an orphan nuclear receptor with broad, structural similarities to classical ER that is widely implicated in the transcriptional regulation of energy homeostasis. We have previously demonstrated that ERRγ induces resistance to TAM in ER+ breast cancer models, and that the receptor’s transcriptional activity is modified by activation of the ERK/MAPK pathway. We hypothesize that hyper-activation or over-expression of ERRγ induces a pro-survival transcriptional program that impairs the ability of TAM to inhibit the growth of ER+ breast cancer. The goal of the present study is to determine whether ERRγ target genes are associated with reduced distant metastasis-free survival (DMFS) in ER+ breast cancer treated with TAM. Raw gene expression data was obtained from 3 publicly available breast cancer clinical studies of women with ER+ breast cancer who received TAM as their sole endocrine therapy. ERRγ target genes were selected from 2 studies that published validated chromatin immunoprecipitation (ChIP) analyses of ERRγ promoter occupancy. Kaplan-Meier estimation was used to determine the association of ERRγ target genes with DMFS, and selected genes were validated in ER+, MCF7 breast cancer cells that express exogenous ERRγ. Thirty-seven validated receptor target genes were statistically significantly altered in women who experienced a DM within 5 years, and could classify several independent studies into poor vs. good DMFS. Two genes (EEF1A2 and PPIF) could similarly separate ER+, TAM-treated breast tumors by DMFS, and their protein levels were measured in an ER+ breast cancer cell line model with exogenous ERRγ. Finally, expression of ERRγ and these two target genes are elevated in models of ER+ breast cancer with hyperactivation of ERK/MAPK. ERRγ signaling is associated with poor DMFS in ER+, TAM-treated breast cancer, and ESRRG, EEF1A2, and PPIF comprise a 3-gene signaling node that may contribute to TAM resistance in the context of an active ERK/MAPK pathway.
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影响因子：
11.2
作者：
Creighton, CJ;Hilger, AM;El-Ashry, D
通讯作者：
El-Ashry, D
影响因子：
11.2
作者：
Bouker, KB;Skaar, TC;Clarke, R
通讯作者：
Clarke, R
影响因子：
3.7
作者：
Girard BJ;Regan Anderson TM;Welch SL;Nicely J;Seewaldt VL;Ostrander JH
通讯作者：
Ostrander JH
影响因子：
168.9
作者：
Davies, C.;Godwin, J.;Gray, R.;Clarke, M.;Darby, S.;McGale, P.;Wang, Y. C.;Peto, R.;Pan, H. C.;Cutter, D.;Taylor, C.;Ingle, J.
通讯作者：
Ingle, J.
DOI：
10.1186/1756-9966-29-97
发表时间：
2010-07-19
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Lee J;Kim SS
通讯作者：
Kim SS