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

Jinho Lee, Abhinav Tiwari, Victor Shum, Gordon B. Mills, Michael A. Mancini, Oleg A. Igoshin, Gábor Balázsi

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)6839-6849
Number of pages11
JournalNucleic acids research
Volume42
Issue number11
DOIs
StatePublished - Jun 17 2014
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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