Interferon regulatory factor-1 mediates the proapoptotic but not cell cycle arrest effects of the steroidal antiestrogen ICI 182,780 (Faslodex, Fulvestrant)
Interferon regulatory factor-1 mediates the proapoptotic but not cell cycle arrest effects of the steroidal antiestrogen ICI 182,780 (Faslodex, Fulvestrant)
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DOI：
10.1158/0008-5472.can-03-3602
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发表时间：
2004-06-01
期刊：
影响因子：
11.2
通讯作者：
Clarke, R
中科院分区：
文献类型：
--
作者：
Bouker, KB;Skaar, TC;Clarke, R
抗雌激素诱导细胞停滞（细胞周期停滞）和凋亡，但这些终点和调节其诱导的信号传导之间的关系尚不清楚。我们先前已经将转录因子和推定的肿瘤抑制因子IFN调节因子-1（IRF-1）与获得性抗雌激素抗性相关联（Go et al.，Cancer Res，62：3428-3437，2002）。我们现在显示IRF-1在影响雌激素受体阳性抗雌激素敏感模型（MCF-7、T47 D和ZR-75-1）、获得性抗雌激素抵抗模型（MCF 7/LCC 9;雌激素受体阳性）和新生抗雌激素抵抗模型（MDA-MB-231;雌激素受体阴性）中的抗雌激素反应性方面的功能意义。与MCF-7、T47 D和ZR-75-1细胞相比，MCF 7/LCC 9细胞中的基础IRF-1 mRNA表达较低。MCF-7/LCC 9细胞中的IRF-1转录活性比在亲本细胞（MCF-7/LCC 1）中观察到的低18倍，并且与MDA-MB-231细胞中的IRF-1转录活性相当。尽管在敏感细胞中ICI 182，780可诱导IRF-1 mRNA表达，但这种调节在MCF-7/LCC 9中丢失，在MDA-MB-231细胞中不存在。IRF-1调节的丧失似乎特异于抗雌激素抗性细胞诱导IRF-1 mRNA响应细胞毒性药物阿霉素。显性阴性IRF-1消除ICI 182，780诱导的凋亡反应（降低>4倍），并降低MCF-7和T47 D细胞对ICI 182，780抗增殖作用的敏感性。这种作用不是由细胞周期分布的变化介导的;相反，显性负性IRF-1减少ICI 182，780诱导的细胞凋亡。这些数据确定了一种新的抗雌激素抵抗机制，并暗示IRF-1作为一个关键组成部分，在信号的一些ER介导的影响细胞凋亡/细胞存活。
Antiestrogens induce both cytostasis (cell cycle arrest) and apoptosis, but the relationship between these end points and the signaling that regulates their induction are unclear. We have previously implicated the transcription factor and putative tumor suppressor IFN regulatory factor-1 (IRF-1) in acquired antiestrogen resistance (Go et al., Cancer Res, 62: 3428-3437, 2002). We now show the functional significance of IRF-1 in affecting antiestrogen responsiveness in estrogen receptor-positive antiestrogen-sensitive models (MCF-7, T47D, and ZR-75-1), a model of acquired antiestrogen resistance (MCF7/LCC9; estrogen receptor positive), and a model of de novo antiestrogen resistance (MDA-MB-231; estrogen receptor negative). Basal IRF-1 mRNA expression is lower in MCF7/LCC9 cells when compared with MCF-7, T47D, and ZR-75-1 cells. IRF-1 transcriptional activity in MCF-7/LCC9 cells is 18-fold lower than that seen in the parental cells (MCF-7/LCC1) and is comparable with that in MDA-MB-231 cells. Although IRF-1 mRNA expression is induced by ICI 182,780 in sensitive cells, this regulation is lost in MCF-7/LCC9 and is absent in MDA-MB-231 cells. Loss of IRF-1 regulation appears specific to antiestrogen resistance-resistant cells induce IRF-1 mRNA in response to the cytotoxic drug doxorubicin. A dominant-negative IRF-1 eliminates the ICI 182,780-induced apoptotic response (reduced >4-fold) and reduces MCF-7 and T47D cell sensitivity to the antiproliferative effects of ICI 182,780. This effect is not mediated by changes in cell cycle distribution; rather, dominant-negative IRF-1 reduces ICI 182,780-induced apoptosis. These data identify a novel mechanism of antiestrogen resistance and implicate IRF-1 as a key component in signaling some ER-mediated effects on apoptosis/cell survival.