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

doi:10.1093/nar/gku360

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 journal › Article › peer-review

11 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 language	English (US)
Pages (from-to)	6839-6849
Number of pages	11
Journal	Nucleic acids research
Volume	42
Issue number	11
DOIs	https://doi.org/10.1093/nar/gku360
State	Published - Jun 17 2014
Externally published	Yes

Funding

John S. Dunn Foundation Collaborative Research Award [to O.A.I., G.B. and M.A.M.]; NIGMS 1R01GM106027-01, National Institutes of Health (NIH) DP2 OD006481 04 and NCI U54 CA112970 08 to G.B. and NIGMS R01-GM096189-01 to O.A.I.]; Computational Cancer Biology Training Program fellowship from the W.M. Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia, Cancer Prevention and Research Institute of Texas (CPRIT) [RP101489 to J.L.]; NIH [HD007495, DK56338 and CA125123]; Dan L. Duncan Cancer Center at Baylor College of Medicine. Funding for open access charge: NIGMS 1R01GM106027-01. Conflict of interest statement. None declared.

Funders	Funder number
W.M. Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia
Author National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health The Bev Hartig Huntington's Disease Foundation National Institutes of Health	DP2 OD006481 04
National Institute of Health-National Cancer Institute	U54 CA112970 08, R01-GM096189-01
National Institute of General Medical Sciences	1R01GM106027-01
The National Institute of Child Health and Human Development	P30HD007495
Cancer Prevention and Research Institute of Texas	CA125123, HD007495, DK56338, RP101489
One Baylor Plaza, Baylor College of Medicine

ASJC Scopus subject areas

Genetics

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10.1093/nar/gku360

Cite this

@article{ce294cdf6ba74abc99a82fb0458591c6,

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.",

author = "Jinho Lee and Abhinav Tiwari and Victor Shum and Mills, \{Gordon B.\} and Mancini, \{Michael A.\} and Igoshin, \{Oleg A.\} and G{\'a}bor Bal{\'a}zsi",

note = "Funding Information: John S. Dunn Foundation Collaborative Research Award [to O.A.I., G.B. and M.A.M.]; NIGMS 1R01GM106027-01, National Institutes of Health (NIH) DP2 OD006481 04 and NCI U54 CA112970 08 to G.B. and NIGMS R01-GM096189-01 to O.A.I.]; Computational Cancer Biology Training Program fellowship from the W.M. Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia, Cancer Prevention and Research Institute of Texas (CPRIT) [RP101489 to J.L.]; NIH [HD007495, DK56338 and CA125123]; Dan L. Duncan Cancer Center at Baylor College of Medicine. Funding for open access charge: NIGMS 1R01GM106027-01. Conflict of interest statement. None declared.",

year = "2014",

month = jun,

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doi = "10.1093/nar/gku360",

language = "English (US)",

volume = "42",

pages = "6839--6849",

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T1 - Unraveling the regulatory connections between two controllers of breast cancer cell fate

AU - Lee, Jinho

AU - Tiwari, Abhinav

AU - Shum, Victor

AU - Mills, Gordon B.

AU - Mancini, Michael A.

AU - Igoshin, Oleg A.

AU - Balázsi, Gábor

N1 - Funding Information: John S. Dunn Foundation Collaborative Research Award [to O.A.I., G.B. and M.A.M.]; NIGMS 1R01GM106027-01, National Institutes of Health (NIH) DP2 OD006481 04 and NCI U54 CA112970 08 to G.B. and NIGMS R01-GM096189-01 to O.A.I.]; Computational Cancer Biology Training Program fellowship from the W.M. Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia, Cancer Prevention and Research Institute of Texas (CPRIT) [RP101489 to J.L.]; NIH [HD007495, DK56338 and CA125123]; Dan L. Duncan Cancer Center at Baylor College of Medicine. Funding for open access charge: NIGMS 1R01GM106027-01. Conflict of interest statement. None declared.

PY - 2014/6/17

Y1 - 2014/6/17

N2 - 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.

AB - 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.

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AN - SCOPUS:84903149344

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EP - 6849

JO - Nucleic acids research

JF - Nucleic acids research

IS - 11

ER -

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

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