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首页> 外文期刊>Journal of applied toxicology >Methylparaben stimulates tumor initiating cells in ER plus breast cancer models
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Methylparaben stimulates tumor initiating cells in ER plus breast cancer models

机译：甲基羟基甲苯刺激肿瘤发起细胞在欧尔和乳腺癌模型中

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摘要

A body of epidemiological evidence implicates exposure to endocrine disrupting chemicals (EDCs) with increased susceptibility to breast cancer. To evaluate the physiological effects of a suspected EDC in vivo, we exposed MCF-7 breast cancer cells and a patient-derived xenograft (PDX, estrogen receptor positive) to physiological levels of methylparaben (mePB), which is commonly used in personal care products as a preservative. mePB pellets (4.4g per day) led to increased tumor size of MCF-7 xenografts and ER+ PDX tumors. mePB has been thought to be a xenoestrogen; however, in vitro exposure of 10nM mePB failed to increase MCF-7 cell proliferation or induction of canonical estrogen-responsive genes (pS2 and progesterone receptor), in contrast to 17-estradiol (E2) treatment. MCF-7 and PDX-derived mammospheres exhibited increased size and up-regulation of canonical stem cell markers ALDH1, NANOG, OCT4 and SOX2 when exposed to mePB; these effects were not observed for MDA-MB-231 (ER-) mammospheres. As tumor-initiating cells (TICs) are also believed to be responsible for chemoresistance, mammospheres were treated with either tamoxifen or the pure anti-estrogen fulvestrant in the presence of mePB. Blocking the estrogenic response was not sufficient to block NANOG expression in mammospheres, pointing to a non-classic estrogen response or an ER-independent mechanism of mePB promotion of mammosphere activity. Overall, these results suggest that mePB increases breast cancer tumor proliferation through enhanced TIC activity, in part via regulation of NANOG, and that mePB may play a direct role in chemoresistance by modulating stem cell activity. Copyright (c) 2016 John Wiley & Sons, Ltd.
机译：流行病学证据的身体暗示暴露于内分泌破坏化学品（EDC），随着对乳腺癌的易感性增加。为了评估疑似EDC在体内的生理效果，我们将MCF-7乳腺癌细胞和患者衍生的异种移植物（PDX，雌激素受体阳性）暴露于甲基羟基苯（MePB）的生理水平，这通常用于个人护理产品作为一种防腐剂。 MEPB颗粒（4.4g /天）导致MCF-7异种移植物和ER + PDX肿瘤的肿瘤大小增加。 MEPB被认为是Xenoestrogen;然而，与17-雌二醇（E2）处理相比，10nM Mepb的体外暴露未能增加MCF-7细胞增殖或诱导规范雌激素响应基因（PS2和孕酮受体）。 MCF-7和PDX衍生的乳腺源源在暴露于MEPB时表现出规范干细胞标记Ald1，Nanog，Oct4和Sox2的增加和上调;对于MDA-MB-231（ER-）乳房管未观察到这些效果。作为肿瘤引发细胞（TICS）也被认为是对化学抑制的负责，在MEPB存在下用Tamoxifen或纯抗雌激素氟斯特提治疗静脉XIMPHERES。阻断雌激素反应不足以阻止哺乳动物中的纳米表达，指向非经典的雌激素反应或MEPB促进哺乳动物活性的ER无关的机制。总体而言，这些结果表明MEPB通过增强的TIC活性提高乳腺癌肿瘤增殖，部分通过调节纳米，并且MEPB可以通过调节干细胞活性来在化学化中发挥直接作用。版权所有（c）2016 John Wiley＆Sons，Ltd。

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