Low levels of 3,3'-diindolylmethane activate estrogen receptor α and induce proliferation of breast cancer cells in the absence of estradiol.
Low levels of 3,3'-diindolylmethane activate estrogen receptor α and induce proliferation of breast cancer cells in the absence of estradiol.
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DOI：
10.1186/1471-2407-14-524
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发表时间：
2014-07-21
期刊：
影响因子：
3.8
通讯作者：
Gaudreau L
中科院分区：
文献类型：
--
作者：
Marques M;Laflamme L;Benassou I;Cissokho C;Guillemette B;Gaudreau L
3,3 ' -二吲哚基甲烷（DIM）是一种酸催化的二聚物-3-甲醇（I3C），一种在十字花科蔬菜中发现的植物化学物质，包括西兰花、球芽甘蓝和卷心菜。DIM是一种芳烃受体（AhR）配体，是一种潜在的抗癌药物，即用于治疗乳腺癌。它还被宣传为一种调节性激素稳态的化合物。本研究利用RNA表达联用染色质免疫沉淀（ChIP）技术在乳腺癌细胞系中研究DIM对雌激素信号的影响。我们进一步利用生长测定，以及荧光活化细胞分选（FACS）测定，以监测细胞生长。在这项研究中，我们报道了“生理可得”浓度的DIM （10 μM）以17β-雌二醇（E2）不依赖的方式激活人乳腺癌细胞系MCF7和T47D中的雌激素受体α (ERα)信号通路。因此，我们观察到ERα靶基因如GREB1和TFF1的诱导，并且在没有E2的情况下，10 μM DIM处理后细胞增殖增加。通过使用ERα特异性抑制剂（ICI 182 780），我们证实了DIM治疗的转录和增殖作用是由ERα介导的。我们进一步发现蛋白激酶A信号通路参与了dim介导的ERα活化。相反，较高浓度的DIM（如50 μM）对细胞的作用与预期相反，即抑制细胞增殖。我们发现了DIM对细胞增殖的意想不到的影响，即通过诱导ERα信号通路刺激细胞生长。重要的是，DIM的这种增殖作用发生在潜在的生理浓度下，可以通过饮食或服用胶囊补充剂来提供。
3,3′-diindolylmethane (DIM) is an acid-catalyzed dimer of idole-3-carbinol (I3C), a phytochemical found in cruciferous vegetables that include broccoli, Brussels sprouts and cabbage. DIM is an aryl hydrocarbon receptor (AhR) ligand and a potential anticancer agent, namely for the treatment of breast cancer. It is also advertised as a compound that regulates sex hormone homeostasis. Here we make use of RNA expression assays coupled to Chromatin Immunoprecipitation (ChIP) in breast cancer cell lines to study the effect of DIM on estrogen signaling. We further make use of growth assays, as well as fluorescence-activated cell sorting (FACS) assays, to monitor cell growth. In this study, we report that ‘physiologically obtainable’ concentrations of DIM (10 μM) activate the estrogen receptor α (ERα) signaling pathway in the human breast cancer cell lines MCF7 and T47D, in a 17β-estradiol (E2)-independent manner. Accordingly, we observe induction of ERα target genes such as GREB1 and TFF1, and an increase in cellular proliferation after treatment with 10 μM DIM in the absence of E2. By using an ERα specific inhibitor (ICI 182 780), we confirm that the transcriptional and proliferative effects of DIM treatment are mediated by ERα. We further show that the protein kinase A signaling pathway participates in DIM-mediated activation of ERα. In contrast, higher concentrations of DIM (e.g. 50 μM) have an opposite and expected effect on cells, which is to inhibit proliferation. We document an unexpected effect of DIM on cell proliferation, which is to stimulate growth by inducing the ERα signaling pathway. Importantly, this proliferative effect of DIM happens with potentially physiological concentrations that can be provided by the diet or by taking caplet supplements.
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DOI：
10.1073/pnas.95.6.2920
发表时间：
1998-03-17
影响因子：
11.1
作者：
Lavinsky, RM;Jepsen, K;Rose, DW
通讯作者：
Rose, DW
DOI：
10.1073/pnas.88.21.9543
发表时间：
1991-11-01
影响因子：
11.1
作者：
BJELDANES, LF;KIM, JY;BRADFIELD, CA
通讯作者：
BRADFIELD, CA
影响因子：
11.2
作者：
Belous, Alexandra R.;Hachey, David L.;Parl, Fritz F.
通讯作者：
Parl, Fritz F.
影响因子：
1.8
作者：
Gross-Steinmeyer, K;Stapleton, PL;Eaton, DL
通讯作者：
Eaton, DL
影响因子：
4.8
作者：
Abbott, DW;Ivanova, VS;Ausió, J
通讯作者：
Ausió, J