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The orphan nuclear receptor estrogen-related receptor beta (ERRβ) in triple-negative breast cancer.
Breast Cancer Research and Treatment ( IF 3.8 ) Pub Date : 2019-11-19 , DOI: 10.1007/s10549-019-05485-5
Aileen I Fernandez 1, 2 , Xue Geng 1 , Krysta Chaldekas 1 , Brent Harris 1 , Anju Duttargi 1 , V Layne Berry 1 , Deborah L Berry 1 , Akanksha Mahajan 1 , Luciane R Cavalli 1, 3 , Balázs Győrffy 4 , Ming Tan 1 , Rebecca B Riggins 1, 2
Affiliation  

PURPOSE Triple-negative breast cancer (TNBC)/basal-like breast cancer (BLBC) is a highly aggressive form of breast cancer. We previously reported that a small molecule agonist ligand for the orphan nuclear receptor estrogen-related receptor beta (ERRβ or ESRRB) has growth inhibitory and anti-mitotic activity in TNBC cell lines. In this study, we evaluate the association of ESRRB mRNA, copy number levels, and protein expression with demographic, clinicopathological, and gene expression features in breast tumor clinical specimens. METHODS ESRRB mRNA-level expression and clinical associations were analyzed using RNAseq data. Array-based comparative genomic hybridization determined ESRRB copy number in African-American and Caucasian women. Transcription factor activity was measured using promoter-reporter luciferase assays in TNBC cell lines. Semi-automatic quantification of immunohistochemistry measured ERRβ protein expression on a 150-patient tissue microarray series. RESULTS ESRRB mRNA expression is significantly lower in TNBC/BLBC versus other breast cancer subtypes. There is no evidence of ESRRB copy number loss. ESRRB mRNA expression is correlated with the expression of genes associated with neuroactive ligand-receptor interaction, metabolic pathways, and deafness. These genes contain G/C-rich transcription factor binding motifs. The ESRRB message is alternatively spliced into three isoforms, which we show have different transcription factor activity in basal-like versus other TNBC cell lines. We further show that the ERRβ2 and ERRβsf isoforms are broadly expressed in breast tumors at the protein level. CONCLUSIONS Decreased ESRRB mRNA expression and distinct patterns of ERRβ isoform subcellular localization and transcription factor activity are key features in TNBC/BLBC.

中文翻译:

三阴性乳腺癌中的孤儿核受体雌激素相关受体β(ERRβ)。

目的三阴性乳腺癌(TNBC)/基底样乳腺癌(BLBC)是一种高度侵袭性的乳腺癌。我们先前曾报道,孤儿核受体雌激素相关受体β(ERRβ或ESRRB)的小分子激动剂配体在TNBC细胞系中具有生长抑制和抗有丝分裂活性。在这项研究中,我们评估了乳腺肿瘤临床标本中ESRRB mRNA,拷贝数水平和蛋白质表达与人口统计学,临床病理和基因表达特征之间的关系。方法使用RNAseq数据分析ESRRB mRNA水平的表达和临床关联。基于阵列的比较基因组杂交确定了非洲裔美国人和白人妇女中ESRRB的拷贝数。在TNBC细胞系中使用启动子-报告荧光素酶测定法测量转录因子活性。免疫组织化学的半自动定量检测在150位患者的组织微阵列系列上的ERRβ蛋白表达。结果TNBC / BLBC中的ESRRB mRNA表达明显低于其他乳腺癌亚型。没有证据表明ESRRB副本号丢失。ESRRB mRNA表达与与神经活性配体-受体相互作用,代谢途径和耳聋相关的基因表达相关。这些基因包含富含G / C的转录因子结合基序。将ESRRB信息剪接成三种同工型,我们发现它们与其他TNBC细胞系相比在基底样中具有不同的转录因子活性。我们进一步表明,ERRβ2和ERRβsf亚型在蛋白质水平的乳腺肿瘤中广泛表达。
更新日期:2019-11-01
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