AKT alters genome-wide estrogen receptor α binding and impacts estrogen signaling in breast cancer

Poornima Bhat-Nakshatri, Guohua Wang, Hitesh Appaiah, Nikhil Luktuke, Jason S. Carroll, Tim R. Geistlinger, Myles Brown, Sunil Badve, Yunlong Liu, Harikrishna Nakshatri

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Estrogen regulates several biological processes through estrogen receptor α (ERα) and ERα. ERα-estrogen signaling is additionally controlled by extracellular signal activated kinases such as AKT. In this study, we analyzed the effect of AKT on genome-wide ERα binding in MCF-7 breast cancer cells. Parental and AKT-overexpressing cells displayed 4,349 and 4,359 ERα binding sites, respectively, with ∼60% overlap. In both cell types, ∼40% of estrogen-regulated genes associate with ERα binding sites; a similar percentage of estrogen-regulated genes are differentially expressed in two cell types. Based on pathway analysis, these differentially estrogen-regulated genes are linked to transforming growth factor β (TGF-β), NF-κB, and E2F pathways. Consistent with this, the two cell types responded differently to TGF-β treatment: parental cells, but not AKT-overexpressing cells, required estrogen to overcome growth inhibition. Combining the ERα DNA-binding pattern with gene expression data from primary tumors revealed specific effects of AKT on ERα binding and estrogen-regulated expression of genes that define prognostic subgroups and tamoxifen sensitivity of ERα-positive breast cancer. These results suggest a unique role of AKT in modulating estrogen signaling in ERα-positive breast cancers and highlights how extracellular signal activated kinases can change the landscape of transcription factor binding to the genome.

Original languageEnglish
Pages (from-to)7487-7503
Number of pages17
JournalMolecular and Cellular Biology
Volume28
Issue number24
DOIs
StatePublished - Dec 2008

Fingerprint

Estrogen Receptors
Estrogens
Genome
Breast Neoplasms
Transforming Growth Factors
Phosphotransferases
Binding Sites
Genes
Biological Phenomena
Gene Expression
Tamoxifen
Transcription Factors
DNA
Growth

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

AKT alters genome-wide estrogen receptor α binding and impacts estrogen signaling in breast cancer. / Bhat-Nakshatri, Poornima; Wang, Guohua; Appaiah, Hitesh; Luktuke, Nikhil; Carroll, Jason S.; Geistlinger, Tim R.; Brown, Myles; Badve, Sunil; Liu, Yunlong; Nakshatri, Harikrishna.

In: Molecular and Cellular Biology, Vol. 28, No. 24, 12.2008, p. 7487-7503.

Research output: Contribution to journalArticle

Bhat-Nakshatri, P, Wang, G, Appaiah, H, Luktuke, N, Carroll, JS, Geistlinger, TR, Brown, M, Badve, S, Liu, Y & Nakshatri, H 2008, 'AKT alters genome-wide estrogen receptor α binding and impacts estrogen signaling in breast cancer', Molecular and Cellular Biology, vol. 28, no. 24, pp. 7487-7503. https://doi.org/10.1128/MCB.00799-08
Bhat-Nakshatri P, Wang G, Appaiah H, Luktuke N, Carroll JS, Geistlinger TR et al. AKT alters genome-wide estrogen receptor α binding and impacts estrogen signaling in breast cancer. Molecular and Cellular Biology. 2008 Dec;28(24):7487-7503. https://doi.org/10.1128/MCB.00799-08
Bhat-Nakshatri, Poornima ; Wang, Guohua ; Appaiah, Hitesh ; Luktuke, Nikhil ; Carroll, Jason S. ; Geistlinger, Tim R. ; Brown, Myles ; Badve, Sunil ; Liu, Yunlong ; Nakshatri, Harikrishna. / AKT alters genome-wide estrogen receptor α binding and impacts estrogen signaling in breast cancer. In: Molecular and Cellular Biology. 2008 ; Vol. 28, No. 24. pp. 7487-7503.
@article{1bbd2efee07a4ac4842da6f99abf80be,
title = "AKT alters genome-wide estrogen receptor α binding and impacts estrogen signaling in breast cancer",
abstract = "Estrogen regulates several biological processes through estrogen receptor α (ERα) and ERα. ERα-estrogen signaling is additionally controlled by extracellular signal activated kinases such as AKT. In this study, we analyzed the effect of AKT on genome-wide ERα binding in MCF-7 breast cancer cells. Parental and AKT-overexpressing cells displayed 4,349 and 4,359 ERα binding sites, respectively, with ∼60{\%} overlap. In both cell types, ∼40{\%} of estrogen-regulated genes associate with ERα binding sites; a similar percentage of estrogen-regulated genes are differentially expressed in two cell types. Based on pathway analysis, these differentially estrogen-regulated genes are linked to transforming growth factor β (TGF-β), NF-κB, and E2F pathways. Consistent with this, the two cell types responded differently to TGF-β treatment: parental cells, but not AKT-overexpressing cells, required estrogen to overcome growth inhibition. Combining the ERα DNA-binding pattern with gene expression data from primary tumors revealed specific effects of AKT on ERα binding and estrogen-regulated expression of genes that define prognostic subgroups and tamoxifen sensitivity of ERα-positive breast cancer. These results suggest a unique role of AKT in modulating estrogen signaling in ERα-positive breast cancers and highlights how extracellular signal activated kinases can change the landscape of transcription factor binding to the genome.",
author = "Poornima Bhat-Nakshatri and Guohua Wang and Hitesh Appaiah and Nikhil Luktuke and Carroll, {Jason S.} and Geistlinger, {Tim R.} and Myles Brown and Sunil Badve and Yunlong Liu and Harikrishna Nakshatri",
year = "2008",
month = "12",
doi = "10.1128/MCB.00799-08",
language = "English",
volume = "28",
pages = "7487--7503",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "24",

}

TY - JOUR

T1 - AKT alters genome-wide estrogen receptor α binding and impacts estrogen signaling in breast cancer

AU - Bhat-Nakshatri, Poornima

AU - Wang, Guohua

AU - Appaiah, Hitesh

AU - Luktuke, Nikhil

AU - Carroll, Jason S.

AU - Geistlinger, Tim R.

AU - Brown, Myles

AU - Badve, Sunil

AU - Liu, Yunlong

AU - Nakshatri, Harikrishna

PY - 2008/12

Y1 - 2008/12

N2 - Estrogen regulates several biological processes through estrogen receptor α (ERα) and ERα. ERα-estrogen signaling is additionally controlled by extracellular signal activated kinases such as AKT. In this study, we analyzed the effect of AKT on genome-wide ERα binding in MCF-7 breast cancer cells. Parental and AKT-overexpressing cells displayed 4,349 and 4,359 ERα binding sites, respectively, with ∼60% overlap. In both cell types, ∼40% of estrogen-regulated genes associate with ERα binding sites; a similar percentage of estrogen-regulated genes are differentially expressed in two cell types. Based on pathway analysis, these differentially estrogen-regulated genes are linked to transforming growth factor β (TGF-β), NF-κB, and E2F pathways. Consistent with this, the two cell types responded differently to TGF-β treatment: parental cells, but not AKT-overexpressing cells, required estrogen to overcome growth inhibition. Combining the ERα DNA-binding pattern with gene expression data from primary tumors revealed specific effects of AKT on ERα binding and estrogen-regulated expression of genes that define prognostic subgroups and tamoxifen sensitivity of ERα-positive breast cancer. These results suggest a unique role of AKT in modulating estrogen signaling in ERα-positive breast cancers and highlights how extracellular signal activated kinases can change the landscape of transcription factor binding to the genome.

AB - Estrogen regulates several biological processes through estrogen receptor α (ERα) and ERα. ERα-estrogen signaling is additionally controlled by extracellular signal activated kinases such as AKT. In this study, we analyzed the effect of AKT on genome-wide ERα binding in MCF-7 breast cancer cells. Parental and AKT-overexpressing cells displayed 4,349 and 4,359 ERα binding sites, respectively, with ∼60% overlap. In both cell types, ∼40% of estrogen-regulated genes associate with ERα binding sites; a similar percentage of estrogen-regulated genes are differentially expressed in two cell types. Based on pathway analysis, these differentially estrogen-regulated genes are linked to transforming growth factor β (TGF-β), NF-κB, and E2F pathways. Consistent with this, the two cell types responded differently to TGF-β treatment: parental cells, but not AKT-overexpressing cells, required estrogen to overcome growth inhibition. Combining the ERα DNA-binding pattern with gene expression data from primary tumors revealed specific effects of AKT on ERα binding and estrogen-regulated expression of genes that define prognostic subgroups and tamoxifen sensitivity of ERα-positive breast cancer. These results suggest a unique role of AKT in modulating estrogen signaling in ERα-positive breast cancers and highlights how extracellular signal activated kinases can change the landscape of transcription factor binding to the genome.

UR - http://www.scopus.com/inward/record.url?scp=57349173558&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=57349173558&partnerID=8YFLogxK

U2 - 10.1128/MCB.00799-08

DO - 10.1128/MCB.00799-08

M3 - Article

VL - 28

SP - 7487

EP - 7503

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 24

ER -