IL6/STAT3 Signaling Hijacks Estrogen Receptor α Enhancers to Drive Breast Cancer Metastasis

被引：199

作者：

Siersbaek, Rasmus ^{[1
,10
]}

Scabia, Valentina ^{[2
]}

Nagarajan, Sankari ^{[1
]}

Chernukhin, Igor ^{[1
]}

Papachristou, Evangelia K. ^{[1
]}

Broome, Rebecca ^{[1
]}

Johnston, Simon J. ^{[3
,11
]}

Joosten, Stacey Ep ^{[4
]}

Green, Andrew R. ^{[3
]}

Kumar, Sanjeev ^{[1
,5
]}

Jones, Julia ^{[1
]}

Omarjee, Soleilmane ^{[1
]}

Alvarez-Fernandez, Ruben ^{[1
]}

Glont, Silvia ^{[1
]}

Aitken, Sarah J. ^{[1
,6
,7
]}

Kishore, Kamal ^{[1
]}

Cheeseman, Danya ^{[1
]}

Rakha, Emad A. ^{[3
]}

D'Santos, Clive ^{[1
]}

Zwart, Wilbert ^{[4
,8
,9
]}

Russell, Alasdair ^{[1
]}

Brisken, Cathrin ^{[2
]}

Carroll, Jason S. ^{[1
]}

机构：

[1] Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge CB2 ORE, England

[2] Ecole Polytech Fed Lausanne EPFL, ISREC Swiss Inst Expt Canc Res, Sch Life Sci, CH-1015 Lausanne, Switzerland

[3] Univ Nottingham, Nottingham Breast Canc Res Ctr, Sch Med, Div Canc & Stem Cells,Biodiscovery Inst, Univ Pk, Nottingham NG7 2RD, England

[4] Netherlands Canc Inst, Oncode Inst, Div Oncogen, Amsterdam, Netherlands

[5] Addenbrookes Hosp, Cambridge CB2 0QQ, England

[6] Cambridge Univ Hosp NHS Fdn Trust, Addenbrookes Hosp, Dept Histopathol, Cambridge CB2 0QQ, England

[7] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England

[8] Eindhoven Univ Technol, Dept Biomed Engn, Lab Chem Biol, Eindhoven, Netherlands

[9] Eindhoven Univ Technol, Dept Biomed Engn, Inst Complex Mol Syst, Eindhoven, Netherlands

[10] Univ Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark

[11] AstraZeneca, Translat Med, Cambridge CB2 0AA, England

来源：

CANCER CELL | 2020年 / 38卷 / 03期

基金：

英国惠康基金;

关键词：

ENDOTHELIAL GROWTH-FACTOR; ER-ALPHA; INTERLEUKIN-6; IL-6; STAT3; TRANSCRIPTION; DETERMINANT; RESISTANCE; CYTOKINE; DATABASE;

D O I：

10.1016/j.ccell.2020.06.007

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The cytokine interleukin-6 (IL6) and its downstream effector STAT3 constitute a key oncogenic pathway, which has been thought to be functionally connected to estrogen receptor alpha (ER) in breast cancer. We demonstrate that IL6/STAT3 signaling drives metastasis in ER+ breast cancer independent of ER. STAT3 hijacks a subset of ER enhancers to drive a distinct transcriptional program. Although these enhancers are shared by both STAT3 and ER, IL6/STAT3 activity is refractory to standard ER-targeted therapies. Instead, inhibition of STAT3 activity using the JAK inhibitor ruxolitinib decreases breast cancer invasion in vivo, Therefore, IL6/STAT3 and ER oncogenic pathways are functionally decoupled, highlighting the potential of IL6/STAT3-targeted therapies in ER+ breast cancer.

引用

页码：412 / +

页数：21

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