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A kinetic model identifies phosphorylated estrogen receptor-? (ER?) as a critical regulator of ER? dynamics in breast cancer.

ABSTRACT: Receptor levels are a key mechanism by which cells regulate their response to stimuli. The levels of estrogen receptor-? (ER?) impact breast cancer cell proliferation and are used to predict prognosis and sensitivity to endocrine therapy. Despite the clinical application of this information, it remains unclear how different cellular processes interact as a system to control ER? levels. To address this question, experimental results from the ER?-positive human breast cancer cell line (MCF-7) treated with 17-?-estradiol or vehicle control were used to develop a mass-action kinetic model of ER? regulation. Model analysis determined that RNA dynamics could be captured through phosphorylated ER? (pER?)-dependent feedback on transcription. Experimental analysis confirmed that pER?-S118 binds to the estrogen receptor-1 (ESR1) promoter, suggesting that pER? can feedback on ESR1 transcription. Protein dynamics required a separate mechanism in which the degradation rate for pER? was 8.3-fold higher than nonphosphorylated ER?. Using a model with both mechanisms, the root mean square error was 0.078. Sensitivity analysis of this combined model determined that while multiple mechanisms regulate ER? levels, pER?-dependent feedback elicited the strongest effect. Combined, our computational and experimental results identify phosphorylation of ER? as a critical decision point that coordinates the cellular circuitry to regulate ER? levels.

SUBMITTER: Tian D

PROVIDER: S-EPMC4415015 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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A kinetic model identifies phosphorylated estrogen receptor-α (ERα) as a critical regulator of ERα dynamics in breast cancer.

Tian Dan D Solodin Natalia M NM Rajbhandari Prashant P Bjorklund Kelsi K Alarid Elaine T ET Kreeger Pamela K PK

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20150203 5

Receptor levels are a key mechanism by which cells regulate their response to stimuli. The levels of estrogen receptor-α (ERα) impact breast cancer cell proliferation and are used to predict prognosis and sensitivity to endocrine therapy. Despite the clinical application of this information, it remains unclear how different cellular processes interact as a system to control ERα levels. To address this question, experimental results from the ERα-positive human breast cancer cell line (MCF-7) trea ...[more]

PMID: 25648997

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Project description:BackgroundEstrogen receptor-? (ER?)-negative breast cancer is clinically aggressive and normally does not respond to conventional estrogen target-directed therapies. The soybean isoflavone, genistein (GE), has been shown to prevent and inhibit breast cancer and recent studies have suggested that GE can enhance the anticancer capacity of an estrogen antagonist, tamoxifen (TAM), especially in ER?-positive breast cancer cells. However, the role of GE in ER?-negative breast cancer remains unknown.MethodsWe have evaluated the in vitro and in vivo epigenetic effects of GE on ER? reactivation by using MTT assay, real-time reverse transcription-polymerase chain reaction (RT-PCR) assay, western-blot assay, immunoprecipitation (ChIP) assay, immunohistochemistry and epigenetic enzymatic activity analysis. Preclinical mouse models including xenograft and spontaneous breast cancer mouse models were used to test the efficacy of GE in vivo.ResultsWe found that GE can reactivate ER? expression and this effect was synergistically enhanced when combined with a histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), in ER?-negative MDA-MB-231 breast cancer cells. GE treatment also re-sensitized ER?-dependent cellular responses to activator 17?-estradiol (E2) and antagonist TAM. Further studies revealed that GE can lead to remodeling of the chromatin structure in the ER? promoter thereby contributing to ER? reactivation. Consistently, dietary GE significantly prevented cancer development and reduced the growth of ER?-negative mouse breast tumors. Dietary GE further enhanced TAM-induced anti-cancer efficacy due at least in part to epigenetic ER? reactivation.ConclusionsOur studies suggest that soybean genistein can epigenetically restore ER? expression, which in turn increases TAM-dependent anti-estrogen therapeutic sensitivity in vitro and in vivo. The results from our studies reveal a novel therapeutic combination approach using bioactive soybean product and anti-hormone therapy in refractory ER?-negative breast cancer which will provide more effective options in breast cancer therapy.

Dataset Information

A kinetic model identifies phosphorylated estrogen receptor-? (ER?) as a critical regulator of ER? dynamics in breast cancer.

Publications

A kinetic model identifies phosphorylated estrogen receptor-α (ERα) as a critical regulator of ERα dynamics in breast cancer.

Similar Datasets

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