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

作者：Tian Dan; Solodin Natalia M; Rajbhandari Prashant; Bjorklund Kelsi; Alarid Elaine T; Kreeger Pamela K^*

来源：The FASEB Journal, 2015, 29(5): 2022-2031.

DOI：10.1096/fj.14-265637

• systems biology
• mathematical modeling
• nuclear receptor
• feedback

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.

• 出版日期2015-5