Long-term estradiol deprivation in breast cancer cells up-regulates growth factor signaling and enhances estrogen sensitivity
Long-term estradiol deprivation in breast cancer cells up-regulates growth factor signaling and enhances estrogen sensitivity
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DOI：
10.1677/erc.1.01018
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发表时间：
2005-07-01
影响因子：
3.9
通讯作者：
Yue, W
中科院分区：
文献类型：
--
作者：
Santen, RJ;Song, RX;Yue, W
雌激素的释放导致女性乳腺肿瘤适应并发展对这种类固醇的敏感性增强。因此，卵巢切除术治疗后复发的妇女，这大大降低了雌二醇的延长时间，其次是芳香酶抑制剂与肿瘤消退。我们利用体外和体内模型系统来研究长期雌二醇剥夺（LTED）导致细胞适应并对雌二醇产生超敏反应的生物学过程。有几种机制与这种反应有关，包括雌激素受体α（ER α）和MAP激酶、磷酸肌醇3激酶（P13-K）和哺乳动物雷帕霉素靶蛋白（mTOR）生长因子途径的上调。ER α上调4 - 10倍，并与Shc、Grb-2和Sos共同选择经典的生长因子途径。这诱导了在LTED细胞中增强的快速非基因组效应。参与非基因组信号传导过程的分子已被鉴定。内皮素与细胞膜相关的ER α结合，ER α与接头蛋白Shc物理结合，并诱导其磷酸化。反过来，Shc结合Grb-2和Sos，这导致MAP激酶的快速激活。雌激素的这些非基因组效应会产生生物学效应，Elk-1激活和细胞膜的形态变化就证明了这一点。其他作用包括通过雌二醇诱导ER α与IGF-I和表皮生长因子受体结合激活P13-K和mTOR途径。一个主要的问题是ER α如何定位在质膜上，因为它不包含固有的膜定位信号。我们提供的证据表明，IGF-I受体作为一个锚的ER α在质膜。雌二醇引起衔接蛋白、Shc和IGF-I受体本身的磷酸化。Shc在与ER α结合后，充当将ER α运载到活化的IGF-I受体上的Shc结合位点的“总线”。使用小抑制剂（si）RNA方法敲低Shc允许的结论是，ER α定位在质膜上需要Shc。为了消除生长因子诱导的超敏反应，我们已经利用了一种药物，法尼基硫代水杨酸，它阻断GTP-Ras与其膜受体蛋白，半乳糖凝集素1的结合，并减少MAP激酶的激活。我们还表明，这种药物是一种有效的mTOR抑制剂，作为抑制细胞增殖的另一种机制。“适应性超敏反应”的概念及其机制具有重要的临床意义。芳香化酶抑制剂在他莫昔芬复发患者中的疗效可以通过这种机制来解释，生长因子途径的抑制剂应该逆转超敏反应现象，并延长乳腺癌激素治疗的疗效。
Deprivation of estrogen causes breast tumors in women to adapt and develop enhanced sensitivity to this steroid. Accordingly, women relapsing after treatment with oophorectomy, which substantially lowers estradiol for a prolonged period, respond secondarily to aromatase inhibitors with tumor regression. We have utilized in vitro and in vivo model systems to examine the biologic processes whereby long-term estradiol deprivation (LTED) causes cells to adapt and develop hypersensitivity to estradiol. Several mechanisms are associated with this response, including up-regulation of estrogen receptor-alpha (ER alpha) and the MAP kinase, phosphoinositol 3 kinase (P13-K) and mammalian target of rapamycin (mTOR) growth factor pathways. ER alpha is four- to tenfold up-regulated and co-opts a classical growth factor pathway using Shc, Grb-2 and Sos. This induces rapid non-genomic effects which are enhanced in LTED cells. The molecules involved in the non-genomic signaling process have been identified. Estradiol binds to cell membrane-associated ERa, which physically associates with the adaptor protein Shc, and induces its phosphorylation. In turn, Shc binds Grb-2 and Sos, which result in the rapid activation of MAP kinase. These non-genomic effects of estradiol produce biologic effects as evidenced by Elk-1 activation and by morphologic changes in cell membranes. Additional effects include activation of the P13-K and mTOR pathways through estradiol-induced binding of ER alpha to the IGF-I and epidermal growth factor receptors. A major question is how ER alpha locates in the plasma membrane since it does not contain an inherent membrane localization signal. We have provided evidence that the IGF-I receptor serves as an anchor for ER alpha in the plasma membrane. Estradiol causes phosphorylation of the adaptor protein, Shc and the IGF-I receptor itself. Shc, after binding to ER alpha, serves as the 'bus' which carries ERa to Shc-binding sites on the activated IGF-I receptors. Use of small inhibitor (si) RNA methodology to knockdown Shc allows the conclusion that Shc is needed for ER alpha to localize in the plasma membrane. In order to abrogate growth factor-induced hypersensitivity, we have utilized a drug, farnesylthiosalicylic acid, which blocks the binding of GTP-Ras to its membrane acceptor protein, galectin 1, and reduces the activation of MAP kinase. We have also shown that this drug is a potent inhibitor of mTOR as an additional mechanism of inhibition of cell proliferation. The concept of 'adaptive hypersensitivity' and the mechanisms responsible for this phenomenon have important clinical implications. The efficacy of aromatase inhibitors in patients relapsing on tamoxifen could be explained by this mechanism and inhibitors of growth factor pathways should reverse the hypersensitivity phenomenon and result in prolongation of the efficacy of hormonal therapy for breast cancer.