Macedo Luciana F, Sabnis Gauri, Brodie Angela
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, and the Greenebaum Cancer Center, Baltimore, Maryland.
Cancer. 2008 Feb 1;112(3 Suppl):679-688. doi: 10.1002/cncr.23191.
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 alpha (ER-alpha) levels decreased below control levels in letrozole-resistant tumors. The decrease was simultaneous to an increase in phosphorylation of ER-alpha 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-alpha 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.
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）和抗雌激素药物（AE）的抗肿瘤疗效。尽管AI来曲唑能持续抑制肿瘤生长，但即使持续治疗，肿瘤最终还是开始生长。在本研究中，对治疗过程中来曲唑耐药的机制进行了研究。在对来曲唑耐药的肿瘤中，雌激素受体α（ER-α）水平降至对照水平以下。这种下降与ER-α磷酸化增加以及孕激素受体（PgR）表达未改变同时发生。HER-2、活化的（磷酸化的）SHC衔接蛋白（p-Shc）、生长因子受体结合蛋白2（Grb-2）、p-Raf、磷酸化的丝裂原活化蛋白激酶激酶1/2（p-Mek1/2）和磷酸化的丝裂原活化蛋白激酶（p-MAPK）的表达水平均升高。当用HER-2信号通路抑制剂处理从来曲唑耐药肿瘤中分离出的细胞（LTLTCa细胞）时，ER-α表达和雌二醇刺激的反式激活得以恢复。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信号之间存在相互作用。为了防止HER-2通路激活和对AI耐药，用AI与ER下调剂氟维司群联合治疗小鼠。HER-2或p-MAPK表达没有增加，肿瘤生长受到显著抑制。当在来曲唑治疗下对无反应的肿瘤添加曲妥珠单抗时，与单独改用曲妥珠单抗相比，它能显著抑制肿瘤生长。然而，曲妥珠单抗加来曲唑联合治疗仅在难治性乳腺癌中比单独使用来曲唑更有效。这些结果表明，阻断ER和HER-2信号可能会延缓复发性乳腺癌患者对AI耐药的发生。
