title: Unraveling the regulatory connections between two controllers of breast cancer cell fate.
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.
authors.affiliation: Department of Systems Biology - Unit 950, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA Department of Bioengineering, Rice University, Houston, TX 77005, USA.
authors.forename: Jinho
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Bioengineering, Rice University, Houston, TX 77005, USA.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Tiwari
authors.affiliation: Department of Systems Biology - Unit 950, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA Department of Physics, University of Houston, Houston, TX 77004, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Shum
authors.affiliation: Department of Systems Biology - Unit 950, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Mancini
authors.affiliation: Department of Bioengineering, Rice University, Houston, TX 77005, USA igoshin@rice.edu.
authors.forename: Oleg A
authors.initials: OA
authors.lastname: Igoshin
authors.affiliation: Department of Systems Biology - Unit 950, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA gbalazsi@mdanderson.org gabor@laufercenter.org.
authors.forename: Gábor
authors.initials: G
authors.lastname: Balázsi
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D005260:Female; D050990:GATA3 Transcription Factor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D008957:Models, Genetic
chemical_list: D047628:Estrogen Receptor alpha; D050990:GATA3 Transcription Factor