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

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-G...

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Bibliographic Details
Published in:Nucleic acids research 2014-06, Vol.42 (11), p.6839-6849
Main Authors: Lee, Jinho, Tiwari, Abhinav, Shum, Victor, Mills, Gordon B, Mancini, Michael A, Igoshin, Oleg A, Balázsi, Gábor
Format: Article
Language:English
Subjects:
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Cell Line, Tumor
Computational Biology
Estrogen Receptor alpha - biosynthesis
Estrogen Receptor alpha - genetics
Estrogen Receptor alpha - metabolism
Feedback, Physiological
Female
GATA3 Transcription Factor - biosynthesis
GATA3 Transcription Factor - genetics
GATA3 Transcription Factor - metabolism
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
Humans
Models, Genetic
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Summary: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.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gku360