Unique Roles of p160 Coactivators for Regulation of Breast Cancer Cell Proliferation and Estrogen Receptor-α Transcriptional Activity
Unique Roles of p160 Coactivators for Regulation of Breast Cancer Cell Proliferation and Estrogen Receptor-α Transcriptional Activity
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DOI：
10.1210/en.2008-1001
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发表时间：
2009-04-01
期刊：
影响因子：
4.8
通讯作者：
Smith, Carolyn L.
中科院分区：
文献类型：
--
作者：
Karmakar, Sudipan;Foster, Estrella A.;Smith, Carolyn L.
在反式激活试验中，p160类固醇受体共激活因子（SRC）家族的三个成员（SRC-1、SRC-2和SRC-3）均刺激雌激素受体（ER）-α功能。因此，我们试图阐明它们对ER调节的细胞增殖、凋亡和MCF-7乳腺癌细胞中ER α靶基因表达过程的贡献。SRC-2或SRC-3而非SRC-1的小干扰RNA消耗抑制MCF-7细胞的生长，并且这反映在SRC-2或SRC-3消耗的细胞中细胞周期进展减少和细胞凋亡增加以及在合成报告基因上测量的ER α转录活性降低。然而，只有SRC-3耗竭阻断雌二醇刺激的细胞增殖。SRC-1的消耗不影响这些事件，并且这一起揭示了三种SRC家族共激活因子中的每一种之间的功能差异。内源性ER α靶基因c-myc的调节不受任何p160共激活因子的消耗的影响，尽管它们中的每一个的消耗降低了雌二醇处理的MCF-7细胞中pS2 mRNA的表达。此外，孕激素受体和细胞周期蛋白D1基因表达减少SRC-3小干扰RNA处理的细胞。抗凋亡基因Bcl-2的mRNA和蛋白水平的表达依赖于SRC-3的表达，而Bcl-2蛋白而不是mRNA的表达也对SRC-1的消耗敏感。总之，这些数据表明，密切相关的p160辅激活因子在乳腺癌细胞中不是功能冗余的，因为它们在调节mRNA和蛋白质表达中发挥基因特异性作用，因此它们可能对乳腺肿瘤发生做出独特的贡献。（内分泌学150：1588-1596，2009）
Each of the three members of the p160 steroid receptor coactivator (SRC) family of coactivators (SRC-1, SRC-2 and SRC-3) stimulates estrogen receptor (ER)-alpha function in trans-activation assays. Consequently, we sought to elucidate their contributions to the ER-regulated processes of cell proliferation, apoptosis, and the expression of ER alpha target genes in MCF-7 breast cancer cells. The small interfering RNA depletion of SRC-2 or SRC-3 but not SRC-1 inhibited growth of MCF-7 cells, and this was reflected in decreased cell cycle progression and increased apoptosis in SRC-2-or SRC-3-depleted cells as well as a reduction in ER alpha transcriptional activity measured on a synthetic reporter gene. However, only SRC-3 depletion blocked estradiol stimulated cell proliferation. Depletion of SRC-1 did not affect these events, and together this reveals functional differences between each of the three SRC family coactivators. Regulation of the endogenous ER alpha target gene, c-myc was not affected by depletion of any of the p160 coactivators although depletion of each of them decreased pS2 mRNA expression in estradiol-treated MCF-7 cells. Moreover, progesterone receptor and cyclin D1 gene expression were decreased in SRC-3 small interfering RNA-treated cells. Expression of mRNA and protein levels for the antiapoptotic gene, Bcl-2 was dependent on SRC-3 expression, whereas Bcl-2 protein but not mRNA expression also was sensitive to SRC-1 depletion. Together these data indicate that the closely related p160 coactivators are not functionally redundant in breast cancer cells because they play gene-specific roles in regulating mRNA and protein expression, and they therefore are likely to make unique contributions to breast tumorigenesis. (Endocrinology 150: 1588-1596, 2009)