Year: 2014
Type: article
Abstract: Estrogen receptor alpha (ERα) expression is critical for breast cancer classification, high ERα expression being associated with better prognosis. ERα levels strongly correlate with that of GATA binding protein 3 (GATA3), a major regulator of ERα expression. However, the mechanistic details of ERα-GATA3 regulation remain incompletely understood. Here we combine mathematical modeling with perturbation experiments to unravel the nature of regulatory connections in the ERα-GATA3 network. Through cell population-average, single-cell and single-nucleus measurements, we show that the cross-regulation between ERα and GATA3 amounts to overall negative feedback. Further, mathematical modeling reveals that GATA3 positively regulates its own expression and that ERα autoregulation is most likely absent. Lastly, we show that the two cross-regulatory connections in the ERα-GATA3 negative feedback network decrease the noise in ERα or GATA3 expression. This may ensure robust cell fate maintenance in the face of intracellular and environmental fluctuations, contributing to tissue homeostasis in normal conditions, but also to the maintenance of pathogenic states during cancer progression.
Source: Nucleic Acids Research
DOI: 10.1093/nar/gku360
Authors: J. Lee, A. Tiwari, V. Shum, G. B. Mills, M. A. Mancini, O. A. Igoshin, G. Balazsi
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,992
Funders: Cancer Prevention and Research Institute of Texas, John S. Dunn Foundation, National Institutes of Health, University of Texas MD Anderson Cancer Center, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1081826082, G1248842723, G128840436, G1690115124, Research Training Award, G2408464258, G2557638927, G274084553, Feedback regulation and transcirptional coupling in bacterial stress-response, G3470012156, G3643660333, G5465708471, G579812685, Spatially-delineated System-level Analyses and Control of Cytoskeletal Regulation, G7523309225, G7837447426, Texas Medical Center Digestive Diseases Center, Baylor College of Medicine Cancer Center - Cancer Center Support Grant, Model-based predictions of responses RTK Pathway therapies
OpenAlex ID: W2135341978