Preclinical modeling of endocrine response and resistance: Focus on aromatase inhibitors
Preclinical modeling of endocrine response and resistance: Focus on aromatase inhibitors
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DOI：
10.1002/cncr.23191
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发表时间：
2008-02-01
期刊：
影响因子：
6.2
通讯作者：
Brodie, Angela
中科院分区：
文献类型：
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作者：
Macedo, Luciana F.;Sabnis, Gauri;Brodie, Angela
作者开发了一种乳腺癌瘤内芳香化酶模型系统，以比较几种芳香化酶抑制剂（AI）和抗雌激素（AE）的抗肿瘤疗效。尽管AI来曲唑引起持续的生长抑制，但肿瘤最终开始生长，即使在维持治疗时也是如此。在本研究中，对治疗过程中来曲唑耐药的机制进行了研究。来曲唑耐药肿瘤中雌激素受体a（ER-a）水平低于对照水平。这种减少与ER-α磷酸化的增加和孕酮受体（PgR）的表达不变同时发生。HER-2、活化（磷酸化）SHC-衔接蛋白（p-Shc）、生长因子受体结合蛋白2（Grb-2）、p-Raf、磷酸化丝裂原活化蛋白激酶激酶1/2（p-Mekl/2）和磷酸化丝裂原活化蛋白激酶（p-MAPK）的表达水平升高。当用HER-2信号传导途径的抑制剂处理从来曲唑抗性肿瘤分离的细胞（LTLTCa细胞）时，ER-α表达和雌二醇刺激的反式激活恢复。HER-2阻断剂曲妥珠单抗也恢复了LTLTCa细胞对AI和AE的敏感性。这些发现表明ER和HER-2信号之间存在串扰。为了防止HER-2通路的活化和对AI的抗性，用AI和ER下调剂氟维司群的组合处理小鼠。HER-2和p-MAPK表达无明显增加，肿瘤生长明显抑制。当曲妥珠单抗加入到来曲唑治疗下无反应的肿瘤中时，与转换为单独的曲妥珠单抗相比，其显著抑制肿瘤生长。然而，曲妥珠单抗加来曲唑联合治疗仅在难治性乳腺肿瘤中比来曲唑单药治疗更有效。这些结果表明，阻断ER和HER-2信号可能会延迟复发性乳腺癌患者对AI的耐药性。
The authors developed a breast cancer intratumoral aromatase model system to compare the antitumor efficacy of several aromatase inhibitors (AIs) and antiestrogens (AEs). Although the AI letrozole caused sustained growth inhibition, tumors eventually began to grow, even when treatment was maintained. For the current study, the mechanisms of resistance to letrozole during the course of treatment were investigated. Estrogen receptor a (ER-a) levels decreased below control levels in letrozole-resistant tumors. The decrease was simultaneous to an increase in phosphorylation of ER-a and an unaltered expression of progesterone receptor (PgR). Expression levels of HER-2, activated (phosphorylated) SHC-adaptor protein (p-Shc), growth factor receptor-bound protein 2 (Grb-2), p-Raf, phosphorylated mitogen-activated protein kinase kinase 1/2 (p-Mekl/2), and phosphorylated mitogen-activated protein kinase (p-MAPK) were increased. when cells isolated from letrozole-resistant tumors (LTLTCa cells) were treated with inhibitors of the HER-2 signaling pathway, ER-a expression and estradiol-stimulated transactivation was restored. The HER-2 blocker trastuzumab also restored the sensitivity of LTLTCa cells to AIs and AEs. These findings suggested that there is crosstalk between ER and HER-2 signaling. To prevent activation of the HER-2 pathway and resistance to AIs, mice were treated with a combination of AIs and the ER down-regulator fulvestrant. There was no increase in HER-2 or p-MAPK expression, and tumor growth was inhibited significantly. when trastuzumab was added to unresponsive tumors under letrozole treatment, it significantly inhibited tumors growth compared with switching to trastuzumab alone. However, the trastuzumab plus letrozole combination was more effective than letrozole alone only in refractory breast tumors. These results suggested that blocking both ER and HER-2 signaling may delay the development of resistance to AIs in patients with recurrent breast cancer.