Mouse ER+/PIK3CAH1047R breast cancers caused by exogenous estrogen are heterogeneously dependent on estrogen and undergo BIM-dependent apoptosis with BH3 and PI3K agents.
Mouse ER+/PIK3CAH1047R breast cancers caused by exogenous estrogen are heterogeneously dependent on estrogen and undergo BIM-dependent apoptosis with BH3 and PI3K agents.
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由外源雌激素引起的小鼠 ER /PIK3CAH1047R 乳腺癌对雌激素具有异质依赖性，并在 BH3 和 PI3K 药物的作用下经历 BIM 依赖性细胞凋亡。
DOI：
10.1038/s41388-018-0436-4
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发表时间：
2019
期刊：
影响因子：
8
通讯作者：
Parsons,Ramon
中科院分区：
文献类型：
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作者：
Stratikopoulos,EliasE;Kiess,Nicole;Szabolcs,Matthias;Pegno,Sarah;Kakit,Cheung;Wu,Xuewei;Poulikakos,PoulikosI;Cheung,Pamela;Schmidt,Hank;Parsons,Ramon
雌激素依赖是ER +乳腺癌的主要驱动因素，与PI3K突变相关。PI3K抑制（PI3Ki）可以恢复一些激素治疗耐药ER +乳腺癌对ER信号传导的依赖性，但在其他人中无效。在这里，我们发现短期补充雌激素强烈增强了Pik3caH1047R −诱导的小鼠乳腺肿瘤发生，导致ER +肿瘤，证明了激素和癌基因在肿瘤发展中的合作。与诊断时内分泌依赖性或内分泌非依赖性的人ER +乳腺癌相似，来自该模型的肿瘤系保留ER表达，但对激素治疗敏感或耐药。PI3Ki不诱导细胞死亡，但确实引起促凋亡基因BIM的上调。BH3模拟物或PI3Ki不能恢复几种耐药小鼠和人肿瘤系的激素敏感性。然而，重要的是，PI3Ki和BH 3模拟物的组合在PIK3CA突变型癌细胞中具有深刻的BM依赖性细胞毒性作用，同时保留正常细胞。我们认为，添加BH3模拟物提供了一种治疗策略，可显著改善激素治疗耐药和ER非依赖性PIK3CA突变型乳腺癌中PI3Ki的细胞毒性活性。
Estrogen dependence is major driver of ER + breast cancer, which is associated with PI3K mutation. PI3K inhibition (PI3Ki) can restore dependence on ER signaling for some hormone therapy-resistant ER + breast cancers, but is ineffective in others. Here we show that short-term supplementation with estrogen strongly enhancedPik3caH1047R−induced mammary tumorigenesis in mice that resulted exclusively in ER + tumors, demonstrating the cooperation of the hormone and the oncogene in tumor development. Similar to human ER + breast cancers that are endocrine-dependent or endocrine-independent at diagnosis, tumor lines from this model retained ER expression but were sensitive or resistant to hormonal therapies. PI3Ki did not induce cell death but did cause upregulation of the pro-apoptotic gene BIM. BH3 mimetics or PI3Ki were unable to restore hormone sensitivity in several resistant mouse and human tumor lines. Importantly however, combination of PI3Ki and BH3 mimetics had a profound, BIM-dependent cytotoxic effect in PIK3CA-mutant cancer cells while sparing normal cells. We propose that addition of BH3 mimetics offers a therapeutic strategy to markedly improve the cytotoxic activity of PI3Ki in hormonal therapy-resistant and ER−independent PIK3CA-mutant breast cancer.
肉毒杆菌神经毒素和破伤风毒素：Lance L. Simpson 编辑，学术出版社，1989 年。89.00 美元（xiii 422 页）ISBN 0 12 644445 5
影响因子：
--
作者：
K. Aktories
通讯作者：
K. Aktories