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FASEB J. 2015 May;29(5):2022-31. doi: 10.1096/fj.14-265637. Epub 2015 Feb 3.

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

Author information

1
*Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin, USA; Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA; and University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA.
2
*Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin, USA; Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA; and University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA kreeger@wisc.edu.

Abstract

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) treated with 17-β-estradiol or vehicle control were used to develop a mass-action kinetic model of ERα regulation. Model analysis determined that RNA dynamics could be captured through phosphorylated ERα (pERα)-dependent feedback on transcription. Experimental analysis confirmed that pERα-S118 binds to the estrogen receptor-1 (ESR1) promoter, suggesting that pERα can feedback on ESR1 transcription. Protein dynamics required a separate mechanism in which the degradation rate for pERα was 8.3-fold higher than nonphosphorylated ERα. 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 ERα levels, pERα-dependent feedback elicited the strongest effect. Combined, our computational and experimental results identify phosphorylation of ERα as a critical decision point that coordinates the cellular circuitry to regulate ERα levels.

KEYWORDS:

feedback; mathematical modeling; nuclear receptor; systems biology

PMID:
25648997
PMCID:
PMC4415015
DOI:
10.1096/fj.14-265637
[Indexed for MEDLINE]
Free PMC Article

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