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

共 50 条

[31] A muscle-specific protein 'myoferlin' modulates IL-6/STAT3 signaling by chaperoning activated STAT3 to nucleus [J].

Yadav, A. ;

Kumar, B. ;

Lang, J. C. ;

Teknos, T. N. ;

Kumar, P. .

ONCOGENE, 2017, 36 (46) :6374-6382

[32] The IL-6/sTaT3 Signaling Pathway Is An Early Target of Manuka Honey-Induced Suppression of Human Breast Cancer Cells [J].

Aryappalli, Priyanka ;

Al-Qubaisi, Sarah S. ;

Attoub, Samir ;

George, Junu A. ;

Arafat, Kholoud ;

Ramadi, Khalil B. ;

Mohamed, Yassir A. ;

Al-Dhaheri, Mezoon M. ;

Al-Sbiei, Ashraf ;

Fernandez-Cabezudo, Maria J. ;

al-Ramadi, Basel K. .

FRONTIERS IN ONCOLOGY, 2017, 7

[33] STAT3 signaling induced by the IL-6 family of cytokines modulates angiogenesis [J].

Rapp, Julian ;

Jung, Malte ;

Klar, Rhena F. U. ;

Wolf, Julian ;

Arnold, Jakob ;

Gorka, Oliver ;

Gross, Olaf ;

Lange, Clemen ;

Agostini, Hansjurgen ;

Schlunck, Guenther ;

Bucher, Felicitas .

JOURNAL OF CELL SCIENCE, 2023, 136 (01)

[34] Over Activation of IL-6/STAT3 Signaling Pathway in Juvenile Dermatomyositis [J].

Zheng, Qi ;

Wang, Zhaoling ;

Tan, Yejun ;

Zhu, Kun ;

Lu, Meiping .

RHEUMATOLOGY AND THERAPY, 2024, 11 (05) :1255-1269

[35] Peripheral IL-6/STAT3 signaling promotes beiging of white fat [J].

Li, Haifang ;

Dong, Mei ;

Liu, Wenhui ;

Gao, Cheng ;

Jia, Yanxin ;

Zhang, Xinzhi ;

Xiao, Xue ;

Liu, Qingxin ;

Lin, Hai .

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 2021, 1868 (10)

[36] IL-6/STAT3 signaling pathway is activated in plasma cell mastitis [J].

Liu, Yang ;

Zhang, Jian ;

Zhou, Yu-Hui ;

Jiang, Yi-Na ;

Zhang, Wei ;

Tang, Xiao-Jiang ;

Ren, Yu ;

Han, Shui-Ping ;

Liu, Pei-Jun ;

Xu, Jing ;

He, Jian-Jun .

INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY, 2015, 8 (10) :12541-12548

[37] Molecular dynamics of STAT3 on IL-6 signaling pathway in living cells [J].

Watanabe, K ;

Saito, K ;

Kinjo, M ;

Matsuda, T ;

Tamura, M ;

Kon, S ;

Miyazaki, T ;

Uede, T .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2004, 324 (04) :1264-1273

[38] STAT3 transcriptional factor activated by reactive oxygen species induces IL6 in starvation-induced autophagy of cancer cells [J].

Yoon, Sarah ;

Woo, Sang Uk ;

Kang, Jung Hee ;

Kim, Kyongmin ;

Kwon, Myung-Hee ;

Park, Sun ;

Shin, Ho-Joon ;

Gwak, Ho-Shin ;

Chwae, Yong-Joon .

AUTOPHAGY, 2010, 6 (08) :1125-1138

[39] Decoding IL-6/STAT3 as a tumor evolutionary Network: Rethinking breast cancer adaptability and treatment [J].

Kumar, Pankaj ;

Mangla, Bharti .

MEDICAL HYPOTHESES, 2025, 198

[40] Evaluation of selected IL6/STAT3 pathway molecules and miRNA expression in chronic obstructive pulmonary disease [J].

Kiszalkiewicz, J. M. ;

Majewski, S. ;

Piotrowski, W. J. ;

Gorski, P. ;

Pastuszak-Lewandoska, D. ;

Migdalska-Sek, M. ;

Brzezianska-Lasota, E. .

SCIENTIFIC REPORTS, 2021, 11 (01)

← 1 2 3 4 5 →