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首页> 外文期刊>Cancer Cell >Targeting BCL-2 with the BH3 Mimetic ABT-199 in Estrogen Receptor-Positive Breast Cancer
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Targeting BCL-2 with the BH3 Mimetic ABT-199 in Estrogen Receptor-Positive Breast Cancer

机译：BH3模拟ABT-199靶向BCL-2在雌激素受体阳性乳腺癌中的作用

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摘要

The prosurvival protein BCL-2 is frequently overexpressed in estrogen receptor (ER)-positive breast cancer. We have generated ER-positive primary breast tumor xenografts that recapitulate the primary tumors and demonstrate that the BH3 mimetic ABT-737 markedly improves tumor response to the antiestrogen tamoxifen. Despite abundant BCL-XL expression, similar efficacy was observed with the BCL-2 selective inhibitor ABT-199, revealing that BCL-2 is a crucial target. Unexpectedly, BH3 mimetics were found to counteract the side effect of tamoxifen-induced endometrial hyperplasia. Moreover, BH3 mimetics synergized with phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors in eliciting apoptosis. Importantly, these two classes of inhibitor further enhanced tumor response in combination therapy with tamoxifen. Collectively, our findings provide a rationale for the clinical evaluation of BH3 mimetics in therapy for breast cancer.
机译：生存蛋白BCL-2在雌激素受体（ER）阳性乳腺癌中经常过表达。我们已经产生了ER阳性的原发性乳腺肿瘤异种移植物，该异种移植物概括了原发性肿瘤，并证明了BH3模拟物ABT-737显着改善了对抗雌激素他莫昔芬的肿瘤反应。尽管有大量的BCL-XL表达，但使用BCL-2选择性抑制剂ABT-199观察到了相似的功效，表明BCL-2是关键的靶标。出乎意料的是，发现BH3模拟物可抵消他莫昔芬诱导的子宫内膜增生的副作用。此外，BH3模拟物与磷脂酰肌醇3-激酶（PI3K）/雷帕霉素（mTOR）抑制剂的哺乳动物靶标协同作用，诱导细胞凋亡。重要的是，这两类抑制剂在与他莫昔芬联合治疗中进一步增强了肿瘤反应。总体而言，我们的发现为乳腺癌治疗中BH3模拟物的临床评估提供了理论依据。

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