Estrogen receptor alpha (ER alpha) expression is critical for breast cancer classification, high ER alpha expression being associated with better prognosis. ER alpha levels strongly correlate with that of GATA binding protein 3 (GATA3), a major regulator of ER alpha expression. However, the mechanistic details of ER alpha-GATA3 regulation remain incompletely understood. Here we combine mathematical modeling with perturbation experiments to unravel the nature of regulatory connections in the ER alpha-GATA3 network. Through cell population-average, single-cell and single-nucleus measurements, we show that the cross-regulation between ER alpha and GATA3 amounts to overall negative feedback. Further, mathematical modeling reveals that GATA3 positively regulates its own expression and that ER alpha autoregulation is most likely absent. Lastly, we show that the two cross-regulatory connections in the ER alpha-GATA3 negative feedback network decrease the noise in ER alpha 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
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