期刊
CLINICAL CANCER RESEARCH
卷 12, 期 7, 页码 2038-2048出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-05-2172
关键词
-
类别
资金
- NCI NIH HHS [CA80163, CA42439, CA73058] Funding Source: Medline
- NIEHS NIH HHS [ES05022] Funding Source: Medline
Purpose: The purpose of this investigation is to determine the effects of physiologic levels (10-50 nmol/L) of 2-methoxyestradiol (2 ME) on the growth of estrogen receptor (ER)-positive breast cancer cells and provide insights into its mechanism (s) of action. Experimental Design: Using the ER alpha-positive breast cancer cells, we studied the effects of 2ME on cell proliferation and cell signaling. Our hypothesis is that 17 beta-estracliol (E-2) and 2ME can affect shared cell signaling pathways, leading to different outcomes in cell proliferation, depending on the absence/presence of E-2. Results: E-2 stimulated the growth of MCF-7 andT-47 D cells and induced Akt phosphorylation, a nongenomic signaling pathway. In the absence of E-2, 10 to 50 nmol/L of 2ME enhanced cell growth and Akt phosphorylation. However, in the presence of E-2, 2ME inhibited E-2-induced cell growth and prevented E2-induced Akt phosphorylation. Confocal microscopic studies showed that 2ME inhibited subcellular distribution of ER alpha in response to E-2 in MCF-7 and T-47D cells. 2ME also down-regulated E2-induced increases in cyclic AMP and ornithine decarboxylase activity. In addition, treatment of MCF-7 cells with 2ME in the presence of E-2 resulted in a decrease in ER alpha level by 72 hours Accelerated down-regulation of ERa may contribute to growth inhibition in the presence of E-2/2ME combinations. In contrast, a concentration of up to 2.5 mu mol/L 2ME had no effect on the growth of ER-negative SK-BR-3 cells, either in the presence or absence of E-2. Conclusions: Our results provide evidence for the nongenomic action of 2ME in ER-positive cells. In the presence of E-2, 2ME suppressed E-2-induced cell growth, Akt signaling, and generation of cyclic AMP, whereas it acted as an estrogen in the absence of E-2. The intriguing growth-stimulatory and growth-inhibitory effects of 2ME on breast cancer cells suggests the need for its selective use in patients.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据