ACTR/AIB1 functions as an E2F1 coactivator to promote breast cancer cell proliferation and antiestrogen resistance
ACTR/AIB1 functions as an E2F1 coactivator to promote breast cancer cell proliferation and antiestrogen resistance
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DOI：
10.1128/mcb.24.12.5157-5171.2004
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发表时间：
2004-06-01
影响因子：
5.3
通讯作者：
Chen, HW
中科院分区：
文献类型：
--
作者：
Louie, MC;Zou, JX;Chen, HW
ACTR（也称为AIB 1、RAC 3、p/CIP、TRAM-1和SRC-3）是核激素受体共激活因子p160家族的成员，其过表达或扩增经常在多种类型的人类肿瘤（包括乳腺癌）中检测到。然而，其在癌细胞增殖中的作用及其潜在机制尚不清楚。在这里，我们表明，过表达的ACTR不仅增强雌激素刺激的细胞增殖，而且更引人注目的是，完全否定了他莫昔芬和纯抗雌激素的细胞周期阻滞作用。出乎意料的是，我们发现ACTR通过其N末端结构域直接与E2 F1相互作用，并被募集到E2 F靶基因启动子。静止细胞中ACTR的升高强烈刺激与G（1）/S转换相关的E2 F应答基因的转录。我们还证明，通过腺病毒载体介导的RNA干扰，ACTR是E2 F1介导的基因表达和雌激素受体（ER）阴性乳腺癌细胞的增殖所必需的。此外，升高的ACTR促进雌激素非依赖性细胞增殖的能力取决于E2 F1的功能以及ACTR和E2 F1之间的关联，而不是ER。因此，我们的研究结果揭示了ACTR在控制乳腺癌细胞增殖中的重要作用，并暗示ACTR-E2 F1途径是抗雌激素抵抗的一种新机制。
Overexpression or amplification of ACTR (also named AIB1, RAC3, p/CIP, TRAM-1, and SRC-3), a member of the p160 family of coactivators for nuclear hormone receptors, has been frequently detected in multiple types of human tumors, including breast cancer. However, its role in cancer cell proliferation and the underlying mechanism are unclear. Here, we show that overexpression of ACTR not only enhances estrogen-stimulated cell proliferation but also, more strikingly, completely negates the cell cycle arrest effect by tamoxifen and pure anti-estrogens. Unexpectedly, we found that ACTR directly interacts, through its N-terminal domain, with E2F1 and is recruited to E2F target gene promoters. Elevation of ACTR in quiescent cells strongly stimulates the transcription of a subset of E2F-responsive genes that are associated with the G(1)/S transition. We also demonstrated, by adenovirus vector-mediated RNA interference, that ACTR is required for E2F1-mediated gene expression and the proliferation of estrogen receptor (ER)-negative breast cancer cells. Moreover, the ability of elevated ACTR to promote estrogen-independent cell proliferation depends on the function of E2F1 and the association between ACTR and E2F1, but not ER. Thus, our results reveal an essential role of ACTR in control of breast cancer cell proliferation and implicate the ACTR-E2F1 pathway as a novel mechanism in antiestrogen resistance.