Farnesoid X receptor inhibits tamoxifen-resistant MCF-7 breast cancer cell growth through downregulation of HER2 expression.
Farnesoid X receptor inhibits tamoxifen-resistant MCF-7 breast cancer cell growth through downregulation of HER2 expression.
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Farnesoid X受体通过下调HER2表达抑制了他莫昔芬耐药的MCF-7乳腺癌细胞的生长。
DOI：
10.1038/onc.2011.124
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发表时间：
2011-09-29
期刊：
影响因子：
8
通讯作者：
Ando, S.
中科院分区：
文献类型：
--
作者：
Giordano, C.;Catalano, S.;Panza, S.;Vizza, D.;Barone, I.;Bonofiglio, D.;Gelsomino, L.;Rizza, P.;Fuqua, S. A. W.;Ando, S.
他莫昔芬（Tam）治疗是雌激素受体α（ERα）阳性乳腺癌患者的一线内分泌治疗。不幸的是，耐药性经常发生，并且通常与膜酪氨酸激酶受体 HER2 的过度表达有关。这就是内分泌疗法和新型抑制剂联合治疗的基本原理，这些抑制剂可减少 HER2 表达和信号传导，从而抑制 Tam 耐药乳腺癌细胞的生长。在这项研究中，我们发现，通过初级胆汁酸鹅去氧胆酸 (CDCA) 或合成激动剂 GW4064 激活法尼醇 X 受体 (FXR)，可抑制 Tam 耐药乳腺癌细胞（称为 MCF-7 TR1）的生长，该细胞被用作获得性 Tam 耐药的“体外”模型。我们的结果表明，CDCA 处理显着降低了 MCF-7 TR1 细胞中贴壁依赖性和贴壁非依赖性表皮生长因子 (EGF) 诱导的生长。此外，Western blot 分析和实时 RT-PCR 的结果表明，CDCA 治疗可降低 Tam 耐药乳腺癌细胞中 HER2 的表达并抑制 EGF 介导的 HER2 和 p42/44 MAPK 磷酸化。使用含有人 HER2 启动子区域的载体进行的瞬时转染实验表明，CDCA 处理可下调 HER2 启动子的基础活性。诱变研究、电泳迁移率变动分析和染色质免疫沉淀分析表明，这是通过抑制 NF-κB 转录因子与其位于 HER2 启动子区域的特定反应元件结合而发生的。总的来说，这些数据表明，FXR 配体依赖性活性，阻断 HER2/MAPK 信号传导，可能克服人类乳腺癌细胞中的抗雌激素耐药性，并可能代表一种新的治疗工具来治疗产生耐药性的乳腺癌患者。
Tamoxifen (Tam) treatment is a first-line endocrine therapy for estrogen receptor α (ERα) positive breast cancer patients. Unfortunately, resistance frequently occurs and is often related with overexpression of the membrane tyrosine kinase receptor HER2. This is the rationale behind combined treatments with endocrine therapy and novel inhibitors that reduce HER2 expression and signaling and thus inhibit Tam-resistant breast cancer cell growth. In this study we show that activation of Farnesoid X Receptor (FXR), by the primary bile acid chenodeoxycholic acid (CDCA) or the synthetic agonist GW4064, inhibited growth of Tam-resistant breast cancer cells (termed MCF-7 TR1), which was used as an “in vitro” model of acquired Tam-resistance. Our results demonstrate that CDCA treatment significantly reduced both anchorage-dependent and anchorage–independent epidermal growth factor (EGF)-induced growth in MCF-7 TR1 cells. Furthermore, results from Western blot analysis and real-time RT-PCR revealed that CDCA treatment reduced HER2 expression and inhibited EGF-mediated HER2 and p42/44 MAPK phosphorylation in these Tam-resistant breast cancer cells. Transient transfection experiments, using a vector containing the human HER2 promoter region, showed that CDCA treatment down-regulated basal HER2 promoter activity. This occurred through an inhibition of NF-κB transcription factor binding to its specific responsive element located in the HER2 promoter region as revealed by mutagenesis studies, electrophoretic mobility shift assay and chromatin immunoprecipitation analysis. Collectively, these data suggest that FXR ligand-dependent activity, blocking HER2/MAPK signaling, may overcome antiestrogen resistance in human breast cancer cells, and could represent a new therapeutic tool to treat breast cancer patients that develop resistance.
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DOI：
10.1186/bcr329
发表时间：
2001
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Hurst HC
通讯作者：
Hurst HC
K303R雌激素受体 - α乳腺癌突变的表达可通过成瘾对PI3K/Akt激酶途径诱导对芳香酶抑制剂的抗性。
影响因子：
11.2
作者：
Barone I;Cui Y;Herynk MH;Corona-Rodriguez A;Giordano C;Selever J;Beyer A;Andò S;Fuqua SA
通讯作者：
Fuqua SA
影响因子：
5.8
作者：
Gradishar, WJ
通讯作者：
Gradishar, WJ
影响因子：
6.4
作者：
Chung, YL;Sheu, ML;Yen, SH
通讯作者：
Yen, SH
影响因子：
45.3
作者：
Gutierrez, MC;Detre, S;Dowsett, M
通讯作者：
Dowsett, M