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Anti-proliferative and gene expression actions of resveratrol in breast cancer cells in vitro.

ABSTRACT: We have used a perfusion bellows cell culture system to investigate resveratrolinduced anti-proliferation/apoptosis in a human estrogen receptor (ER)-negative breast cancer cell line (MDA-MB-231). Using an injection system to perfuse media with stilbene, we showed resveratrol (0.5 - 100 ?M) to decrease cell proliferation in a concentration-dependent manner. Comparison of influx and medium efflux resveratrol concentrations revealed rapid disappearance of the stilbene, consistent with cell uptake and metabolism of the agent reported by others. Exposure of cells to 10 ?M resveratrol for 4 h daily × 6 d inhibited cell proliferation by more than 60%. Variable extracellular acid-alkaline conditions (pH 6.8 - 8.6) affected basal cell proliferation rate, but did not alter anti-proliferation induced by resveratrol. Resveratrol-induced gene expression, including transcription of the most up-regulated genes and pro-apoptotic p53-dependent genes, was not affected by culture pH changes. The microarray findings in the context of induction of anti-proliferation with brief daily exposure of cells to resveratrol-and rapid disappearance of the compound in the perfusion system-are consistent with existence of an accessible initiation site for resveratrol actions on tumor cells, e.g., the cell surface receptor for resveratrol described on integrin ?v?3.

SUBMITTER: Chin YT

PROVIDER: S-EPMC4350334 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Anti-proliferative and gene expression actions of resveratrol in breast cancer cells in vitro.

Chin Yu-Tang YT Hsieh Meng-Ti MT Yang Sheng-Huei SH Tsai Po-Wei PW Wang Shwu-Huey SH Wang Ching-Chiung CC Lee Yee-Shin YS Cheng Guei-Yun GY HuangFu Wei-Chun WC London David D Tang Heng-Yuan HY Fu Earl E Yen Yun Y Liu Leroy F LF Lin Hung-Yun HY Davis Paul J PJ

Oncotarget 20141201 24

We have used a perfusion bellows cell culture system to investigate resveratrolinduced anti-proliferation/apoptosis in a human estrogen receptor (ER)-negative breast cancer cell line (MDA-MB-231). Using an injection system to perfuse media with stilbene, we showed resveratrol (0.5 - 100 μM) to decrease cell proliferation in a concentration-dependent manner. Comparison of influx and medium efflux resveratrol concentrations revealed rapid disappearance of the stilbene, consistent with cell uptake ...[more]

PMID: 25436977

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Project description:We have previously demonstrated that endoxifen is the most important tamoxifen metabolite responsible for eliciting the anti-estrogenic effects of this drug in breast cancer cells expressing estrogen receptor-alpha (ER?). However, the relevance of ER? in mediating endoxifen action has yet to be explored. Here, we characterize the molecular actions of endoxifen in breast cancer cells expressing ER? and examine its effectiveness as an anti-estrogenic agent in these cell lines.MCF7, Hs578T and U2OS cells were stably transfected with full-length ER?. ER? protein stability, dimer formation with ER? and expression of known ER target genes were characterized following endoxifen exposure. The ability of various endoxifen concentrations to block estrogen-induced proliferation of MCF7 parental and ER?-expressing cells was determined. The global gene expression profiles of these two cell lines was monitored following estrogen and endoxifen exposure and biological pathway analysis of these data sets was conducted to identify altered cellular processes.Our data demonstrate that endoxifen stabilizes ER? protein, unlike its targeted degradation of ER?, and induces ER?/ER? heterodimerization in a concentration dependent manner. Endoxifen is also shown to be a more potent inhibitor of estrogen target genes when ER? is expressed. Additionally, low concentrations of endoxifen observed in tamoxifen treated patients with deficient CYP2D6 activity (20 to 40 nM) markedly inhibit estrogen-induced cell proliferation rates in the presence of ER?, whereas much higher endoxifen concentrations are needed when ER? is absent. Microarray analyses reveal substantial differences in the global gene expression profiles induced by endoxifen at low concentrations (40 nM) when comparing MCF7 cells which express ER? to those that do not. These profiles implicate pathways related to cell proliferation and apoptosis in mediating endoxifen effectiveness at these lower concentrations.Taken together, these data demonstrate that the presence of ER? enhances the sensitivity of breast cancer cells to the anti-estrogenic effects of endoxifen likely through the molecular actions of ER?/? heterodimers. These findings underscore the need to further elucidate the role of ER? in the biology and treatment of breast cancer and suggest that the importance of pharmacologic variation in endoxifen concentrations may differ according to ER? expression.

Dataset Information

Anti-proliferative and gene expression actions of resveratrol in breast cancer cells in vitro.

Publications

Anti-proliferative and gene expression actions of resveratrol in breast cancer cells in vitro.

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