Estrogens have been shown to elicit anticancer effects against estrogen receptor α (ER)-positive breast cancer. We sought to determine the mechanism underlying the therapeutic response. Response to 17β-estradiol was assessed in ER+ breast cancer models with resistance to estrogen deprivation: WHIM16 patient-derived xenografts, C7-2-HI and C4-HI murine mammary adenocarcinomas, and long-term estrogen-deprived MCF-7 cells. As another means to reactivate ER, the anti-estrogen fulvestrant was withdrawn from fulvestrant-resistant MCF-7 cells. Transcriptional, growth, apoptosis, and molecular alterations in response to ER reactivation were measured. 17β-estradiol treatment and fulvestrant withdrawal induced transcriptional activation of ER, and cells adapted to estrogen deprivation or fulvestrant were hypersensitive to 17β-estradiol. ER transcriptional response was followed by an unfolded protein response and apoptosis. Such apoptosis was dependent upon the unfolded protein response, p53, and JNK signaling. Anticancer effects were most pronounced in models exhibiting genomic amplification of the gene encoding ER (ESR1), suggesting that engagement of ER at high levels is cytotoxic. These data indicate that long-term adaptation to estrogen deprivation or ER inhibition alters sensitivity to ER reactivation. In such adapted cells, 17β-estradiol treatment and anti-estrogen withdrawal hyperactivate ER, which drives an unfolded protein response and subsequent growth inhibition and apoptosis. 17β-estradiol treatment should be considered as a therapeutic option for anti-estrogen-resistant disease, particularly in patients with tumors harboring ESR1 amplification or ER overexpression. Furthermore, therapeutic strategies that enhance an unfolded protein response may increase the therapeutic effects of ER reactivation.

中文翻译：

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雌激素疗法可诱导未折叠的蛋白质反应，从而驱动ER +乳腺癌中的细胞死亡。

雌激素已显示出对雌激素受体α（ER）阳性乳腺癌的抗癌作用。我们试图确定治疗反应的基础机制。在具有雌激素缺乏抵抗力的ER +乳腺癌模型中评估了对17β-雌二醇的反应：WHIM16患者衍生的异种移植物，C7-2-HI和C4-HI鼠乳腺腺癌以及长期雌激素缺乏的MCF-7细胞。作为重新激活ER的另一种方法，从耐氟维司特的MCF-7细胞中撤出抗雌激素的氟维司汀。测量了转录，生长，凋亡和响应ER激活的分子变化。17β-雌二醇治疗和氟司弗汀撤药诱导了ER的转录激活，适应雌激素剥夺或氟司韦汀的细胞对17β-雌二醇过敏。ER转录反应后是未折叠的蛋白质反应和凋亡。这种细胞凋亡取决于未折叠的蛋白反应，p53和JNK信号传导。在展示编码ER（ESR1）基因的基因组扩增的模型中，抗癌作用最为明显，这表明ER的高水平参与具有细胞毒性。这些数据表明对雌激素剥夺或ER抑制的长期适应改变了对ER重新激活的敏感性。在这种适应性细胞中，17β-雌二醇治疗和抗雌激素戒断可激活ER，从而激活未折叠的蛋白反应，进而抑制生长和凋亡。17β-雌二醇治疗应被视为抗雌激素耐药性疾病的治疗选择，尤其是对于具有ESR1扩增或ER过表达的肿瘤患者。