Interdependency of estradiol-mediated ERα activation and subsequent PR and GREB1 induction to control cell cycle progression

Abstract

Various groups of chemicals that we encounter in every-day life are known to disrupt the endocrine system, such as estrogen mimics that can disturb normal cellular development and homeostasis. To understand the effect of estrogen on intracellular protein dynamics and how this relates to cell proliferation, we aimed to develop a quantitative description of transcription factor complexes and their regulation of cell cycle progression in response to estrogenic stimulation. We designed a mathematical model that describes the dynamics of three proteins, GREB1, PR and TFF1, that are transcriptionally activated upon binding of 17β-estradiol (E2) to estrogen receptor alpha (ERα). Calibration of this model to imaging data monitoring the expression dynamics of these proteins in MCF7 cells suggests that transcriptional activation of GREB1 and PR depends on the association of the E2-ERα complex with both GREB1 and PR. We subsequently combined this ER signaling model with a previously published cell cycle model and compared this to quantification of cell cycle durations in MCF7 cells following nuclei tracking based on images segmented with deep neural networks. The resulting model predicts the effect of GREB1 and PR knockdown on cell cycle progression, thus providing mechanistic insight in the molecular interactions between ERα-regulated proteins and their relation to cell cycle progression. Our findings form a valuable basis to further investigate the pharmacodynamics of endocrine disrupting chemicals and their influence on cellular behavior.