Unraveling the regulatory connections between two controllers of breast cancer cell fate.

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

SUBMITTER: Lee J 

PROVIDER: S-EPMC4066784 | biostudies-other | 2014 Jun

REPOSITORIES: biostudies-other