β2-AR signaling controls trastuzumab resistance-dependent pathway
β2-AR signaling controls trastuzumab resistance-dependent pathway
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β2-AR 信号传导控制曲妥珠单抗耐药依赖性途径
DOI：
10.1038/onc.2015.58
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发表时间：
2016-01-07
期刊：
影响因子：
8
通讯作者：
Guo, N.
中科院分区：
文献类型：
--
作者：
Liu, D.;Yang, Z.;Guo, N.
目前，曲妥珠单抗耐药是治疗人表皮生长因子受体2（Her2）过表达乳腺癌的一个主要临床问题，其潜在的分子机制尚未完全明确。我们先前的研究表明，β2 - 肾上腺素能受体（β2 - AR）和Her2在人乳腺癌细胞中构成一个正反馈回路，并且Her2和β2 - AR之间的相互作用影响乳腺癌细胞的生物学行为，这提示β2 - AR的激活可能参与曲妥珠单抗耐药。在本研究中，我们发现介导大多数儿茶酚胺诱导效应的β2 - AR的表达与Her2过表达乳腺癌患者对曲妥珠单抗的反应呈负相关。儿茶酚胺在体外和体内均能有效拮抗曲妥珠单抗的抗增殖作用。儿茶酚胺刺激通过激活Her2和信号转导及转录激活因子3（STAT3）上调微小RNA - 21（miR - 21）和粘蛋白1（MUC - 1）的表达，导致磷酸酶和张力蛋白同源物缺失以及磷脂酰肌醇 - 3 - 激酶（PI3K）和蛋白激酶B（Akt）的激活。通过抑制微小RNA - 199a/b - 3p，儿茶酚胺诱导哺乳动物雷帕霉素靶蛋白（mTOR）的激活。因此，依赖曲妥珠单抗耐药的PI3K/Akt/mTOR通路受儿茶酚胺诱导的β2 - AR激活所调控。数据表明β2 - AR是预测乳腺癌基于曲妥珠单抗治疗反应可能性的可靠分子标志物。我们还证明β - 受体阻滞剂普萘洛尔不仅增强曲妥珠单抗的抗肿瘤活性，还使耐药细胞对曲妥珠单抗重新敏感。我们的回顾性研究显示，α - 受体阻滞剂和曲妥珠单抗同时治疗显著提高了Her2过表达转移性乳腺癌患者的无进展生存期和总生存期，这暗示了在Her2过表达乳腺癌中曲妥珠单抗联合α - 受体阻滞剂治疗的可能性。
Currently, trastuzumab resistance is a major clinical problem in the treatment of Her2-overexpressing breast cancer. The underlying molecular mechanisms are not fully understood. Our previous study demonstrates that beta 2-adrenergic receptor (beta 2-AR) and Her2 comprise a positive feedback loop in human breast cancer cells and that crosstalk between Her2 and beta 2-AR affects the bio-behaviors of breast cancer cells, suggesting that the beta 2-AR activation may be involved in trastuzumab resistance. In this study, we show that the expression of beta 2-AR, which mediates most catecholamine-induced effects, negatively correlates with trastuzumab response in the patients with Her2-overexpressing breast cancer. Catecholamines potently antagonize the anti-proliferative effects of trastuzumab both in vitro and in vivo. Catecholamine stimulation upregulates the expression of miR-21 and MUC-1 by activating Her2 and STAT3, leading to deficiency of phosphatase and tensin homolog and activation of phosphatidylinositol-3-kinase (PI3K) and Akt. Through inhibition of miR-199a/b-3p, catecholamines induce the mammalian target of rapamycin (mTOR) activation. Thus, trastuzumab resistance-dependent PI3K/Akt/mTOR pathway is controlled by catecholamine-induced beta 2-AR activation. The data indicate that beta 2-AR is a reliable molecular marker for prediction of response probability to trastuzumab-based therapy in breast cancer. We also demonstrate that beta-blocker propranolol not only enhances the antitumor activities of trastuzumab but also re-sensitizes the resistant cells to trastuzumab. Our retrospective study shows that concurrent treatment of a-blocker and trastuzumab significantly improved progression-free survival and overall survival in the patients with Her2-overexpressing metastatic breast cancer, implicating the possibility for combination therapy with trastuzumab plus a-blocker in Her2-overexpressing breast cancer.