Kurokawa H, Arteaga C L
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Clin Cancer Res. 2001 Dec;7(12 Suppl):4436s-4442s; discussion 4411s-4412s.
It has been proposed that binding of ligand to the estrogen receptor (ER) releases its association with transcriptional corepressors, allowing the ER to recruit coactivators, which possess histone acetylase activity, and induce transcription of gene promoters containing estrogen response elements. It has also been proposed that the antiestrogen tamoxifen recruits transcriptional corepressors to the AF-2 region of the hormone-binding domain of the ER, thus blocking ER-mediated transcription. The ER cross-talks with a number of mitogenic signaling pathways and second messengers, like the epidermal growth factor receptor, the insulin-like growth factor-I receptor, mitogen-activated protein (MAP) kinase, phosphatidylinositol-3 kinase/Akt, dopamine, and cyclic AMP. Some of these molecules may: (a) support ligand-independent ER transcription; (b) increase the association of ER with coactivators of transcription; and/or (c) reduce the antiestrogen-induced association of ER with corepressors. These events either alone or in combination may result in hormone independence and/or antiestrogen resistance. We have examined whether signaling by HER2/neu (erbB-2) receptor tyrosine kinase, which can induce antiestrogen resistance, can also disrupt the tamoxifen-induced interaction of ER with transcriptional corepressors. Notably, tamoxifen-induced association of ER with the transcriptional corepressors N-CoR or SMRT was reduced in HER2-overexpressing breast tumor cells but not in cells with low HER2 levels. Small molecule inhibitors of the HER2 kinase or MAP extracellular signal-regulated kinase 1/2 or dominant-negative MAP extracellular signal-regulated kinase 1/2 constructs restored the inhibitory effect of tamoxifen on both ER-mediated transcription and tumor cell proliferation. Treatment with both tamoxifen and the small molecule HER1/2 kinase inhibitor AG1478 reduced mitogen-activated protein kinase activity and markedly reduced growth of established MCF-7/HER2 xenografts in athymic nude mice. Similar results have been obtained with ZD1839 ("Iressa"), an epidermal growth factor receptor (HER1) tyrosine kinase inhibitor. Taken together, these data suggest that exogenous inhibitors of the HER-signaling network and other mitogenic pathways can abrogate or delay the emergence of antiestrogen resistance, thus providing an evaluable therapeutic strategy in human breast carcinoma.
有人提出，配体与雌激素受体（ER）结合会使其与转录共抑制因子解离，使ER能够募集具有组蛋白乙酰化酶活性的共激活因子，并诱导含有雌激素反应元件的基因启动子转录。也有人提出，抗雌激素他莫昔芬会将转录共抑制因子募集到ER激素结合域的AF-2区域，从而阻断ER介导的转录。ER与许多促有丝分裂信号通路和第二信使相互作用，如表皮生长因子受体、胰岛素样生长因子-I受体、丝裂原活化蛋白（MAP）激酶、磷脂酰肌醇-3激酶/Akt、多巴胺和环磷酸腺苷。其中一些分子可能：（a）支持非配体依赖性ER转录；（b）增加ER与转录共激活因子的结合；和/或（c）减少抗雌激素诱导的ER与共抑制因子的结合。这些事件单独或共同作用可能导致激素非依赖性和/或抗雌激素耐药性。我们研究了HER2/neu（erbB-2）受体酪氨酸激酶发出的信号（其可诱导抗雌激素耐药性）是否也能破坏他莫昔芬诱导的ER与转录共抑制因子的相互作用。值得注意的是，在HER2过表达的乳腺肿瘤细胞中，他莫昔芬诱导的ER与转录共抑制因子N-CoR或SMRT的结合减少，但在HER2水平低的细胞中未减少。HER2激酶或MAP细胞外信号调节激酶1/2的小分子抑制剂或显性负性MAP细胞外信号调节激酶1/2构建体恢复了他莫昔芬对ER介导的转录和肿瘤细胞增殖的抑制作用。同时用他莫昔芬和小分子HER1/2激酶抑制剂AG1478处理可降低丝裂原活化蛋白激酶活性，并显著降低无胸腺裸鼠中已建立的MCF-7/HER2异种移植物的生长。用表皮生长因子受体（HER1）酪氨酸激酶抑制剂ZD1839（“易瑞沙”）也得到了类似结果。综上所述，这些数据表明，HER信号网络和其他促有丝分裂途径的外源性抑制剂可以消除或延迟抗雌激素耐药性的出现，从而为人类乳腺癌提供一种可评估的治疗策略。
