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- Title
A kinetic model identifies phosphorylated estrogen receptor-α (ERα) as a critical regulator of ERα dynamics in breast cancer.
- Authors
Tian, Dan; Solodin, Natalia M.; Rajbhandari, Prashant; Bjorklund, Kelsi; Alarid, Elaine T.; Kreeger, Pamela K.
- Abstract
Receptor levels are a key mechanism by which cells regulate their response to stimuli. The levels of estrogen receptor-a (ERα) impact breast cancer cell prolifERαtion and are used to predict prognosis and sensitivity to endocrine thERαpy. Despite the clinical application of this information, it remains unclear how different cellular processes intERαct as a system to control ERα levels. To address this question, experimental results from the ERαpositive human breast cancer cell line (MCF-7) treatedwith 17-β-estradiol or vehicle control were used to develop a mass-action kinetic model of ERα regulation. Model analysis determined thatRNA 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 amodel with both mechanisms, the rootmean 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.
- Subjects
ESTROGEN receptors; BREAST cancer; CANCER cells; HORMONE therapy; CELL lines; PHOSPHORYLATION
- Publication
FASEB Journal, 2015, Vol 29, Issue 5, p2022
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.14-265637