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

Rasmus Siersbæk; Valentina Scabia; Sankari Nagarajan; Igor Chernukhin; Evangelia K. Papachristou; Rebecca Broome; Simon J. Johnston; Stacey E.P. Joosten; Andrew R. Green; Sanjeev Kumar; Julia Jones; Soleilmane Omarjee; Ruben Alvarez-Fernandez; Silvia Glont; Sarah J. Aitken; Kamal Kishore; Danya Cheeseman; Emad A. Rakha; Clive D'Santos; Wilbert Zwart; Alasdair Russell; Cathrin Brisken; Jason S. Carroll

doi:10.1016/j.ccell.2020.06.007

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

Rasmus Siersbæk (Corresponding author), Valentina Scabia, Sankari Nagarajan, Igor Chernukhin, Evangelia K. Papachristou, Rebecca Broome, Simon J. Johnston, Stacey E.P. Joosten, Andrew R. Green, Sanjeev Kumar, Julia Jones, Soleilmane Omarjee, Ruben Alvarez-Fernandez, Silvia Glont, Sarah J. Aitken, Kamal Kishore, Danya Cheeseman, Emad A. Rakha, Clive D'Santos, Wilbert ZwartAlasdair Russell, Cathrin Brisken, Jason S. Carroll

Chemical Biology

Research output: Contribution to journal › Article › Academic › peer-review

44 Citations (Scopus)

Abstract

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 α (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.

Original language	English
Pages (from-to)	412-423.e9
Number of pages	22
Journal	Cancer Cell
Volume	38
Issue number	3
Early online date	16 Jul 2020
DOIs	https://doi.org/10.1016/j.ccell.2020.06.007
Publication status	Published - 14 Sep 2020

Keywords

breast cancer
estrogen receptor
FOXA1
IL6
metastasis
mouse intraductal xenograft model
pioneer factor
STAT3

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2020.06.007

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Siersbæk, R., Scabia, V., Nagarajan, S., Chernukhin, I., Papachristou, E. K., Broome, R., Johnston, S. J., Joosten, S. E. P., Green, A. R., Kumar, S., Jones, J., Omarjee, S., Alvarez-Fernandez, R., Glont, S., Aitken, S. J., Kishore, K., Cheeseman, D., Rakha, E. A., D'Santos, C., ... Carroll, J. S. (2020). IL6/STAT3 Signaling Hijacks Estrogen Receptor α Enhancers to Drive Breast Cancer Metastasis. Cancer Cell, 38(3), 412-423.e9. https://doi.org/10.1016/j.ccell.2020.06.007

Siersbæk, Rasmus ; Scabia, Valentina ; Nagarajan, Sankari ; Chernukhin, Igor ; Papachristou, Evangelia K. ; Broome, Rebecca ; Johnston, Simon J. ; Joosten, Stacey E.P. ; Green, Andrew R. ; Kumar, Sanjeev ; Jones, Julia ; Omarjee, Soleilmane ; Alvarez-Fernandez, Ruben ; Glont, Silvia ; Aitken, Sarah J. ; Kishore, Kamal ; Cheeseman, Danya ; Rakha, Emad A. ; D'Santos, Clive ; Zwart, Wilbert ; Russell, Alasdair ; Brisken, Cathrin ; Carroll, Jason S. / IL6/STAT3 Signaling Hijacks Estrogen Receptor α Enhancers to Drive Breast Cancer Metastasis. In: Cancer Cell. 2020 ; Vol. 38, No. 3. pp. 412-423.e9.

@article{9a7ad21cf1484b848a857fca9a6c5d2c,

title = "IL6/STAT3 Signaling Hijacks Estrogen Receptor α Enhancers to Drive Breast Cancer Metastasis",

abstract = "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 α (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.",

keywords = "breast cancer, estrogen receptor, FOXA1, IL6, metastasis, mouse intraductal xenograft model, pioneer factor, STAT3",

author = "Rasmus Siersb{\ae}k and Valentina Scabia and Sankari Nagarajan and Igor Chernukhin and Papachristou, {Evangelia K.} and Rebecca Broome and Johnston, {Simon J.} and Joosten, {Stacey E.P.} and Green, {Andrew R.} and Sanjeev Kumar and Julia Jones and Soleilmane Omarjee and Ruben Alvarez-Fernandez and Silvia Glont and Aitken, {Sarah J.} and Kamal Kishore and Danya Cheeseman and Rakha, {Emad A.} and Clive D'Santos and Wilbert Zwart and Alasdair Russell and Cathrin Brisken and Carroll, {Jason S.}",

year = "2020",

month = sep,

day = "14",

doi = "10.1016/j.ccell.2020.06.007",

language = "English",

volume = "38",

pages = "412--423.e9",

journal = "Cancer Cell",

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Siersbæk, R, Scabia, V, Nagarajan, S, Chernukhin, I, Papachristou, EK, Broome, R, Johnston, SJ, Joosten, SEP, Green, AR, Kumar, S, Jones, J, Omarjee, S, Alvarez-Fernandez, R, Glont, S, Aitken, SJ, Kishore, K, Cheeseman, D, Rakha, EA, D'Santos, C, Zwart, W, Russell, A, Brisken, C & Carroll, JS 2020, 'IL6/STAT3 Signaling Hijacks Estrogen Receptor α Enhancers to Drive Breast Cancer Metastasis', Cancer Cell, vol. 38, no. 3, pp. 412-423.e9. https://doi.org/10.1016/j.ccell.2020.06.007

IL6/STAT3 Signaling Hijacks Estrogen Receptor α Enhancers to Drive Breast Cancer Metastasis. / Siersbæk, Rasmus (Corresponding author); Scabia, Valentina; Nagarajan, Sankari; Chernukhin, Igor; Papachristou, Evangelia K.; Broome, Rebecca; Johnston, Simon J.; Joosten, Stacey E.P.; Green, Andrew R.; Kumar, Sanjeev; Jones, Julia; Omarjee, Soleilmane; Alvarez-Fernandez, Ruben; Glont, Silvia; Aitken, Sarah J.; Kishore, Kamal; Cheeseman, Danya; Rakha, Emad A.; D'Santos, Clive; Zwart, Wilbert; Russell, Alasdair; Brisken, Cathrin; Carroll, Jason S. (Corresponding author).

In: Cancer Cell, Vol. 38, No. 3, 14.09.2020, p. 412-423.e9.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - IL6/STAT3 Signaling Hijacks Estrogen Receptor α Enhancers to Drive Breast Cancer Metastasis

AU - Siersbæk, Rasmus

AU - Scabia, Valentina

AU - Nagarajan, Sankari

AU - Chernukhin, Igor

AU - Papachristou, Evangelia K.

AU - Broome, Rebecca

AU - Johnston, Simon J.

AU - Joosten, Stacey E.P.

AU - Green, Andrew R.

AU - Kumar, Sanjeev

AU - Jones, Julia

AU - Omarjee, Soleilmane

AU - Alvarez-Fernandez, Ruben

AU - Glont, Silvia

AU - Aitken, Sarah J.

AU - Kishore, Kamal

AU - Cheeseman, Danya

AU - Rakha, Emad A.

AU - D'Santos, Clive

AU - Zwart, Wilbert

AU - Russell, Alasdair

AU - Brisken, Cathrin

AU - Carroll, Jason S.

PY - 2020/9/14

Y1 - 2020/9/14

N2 - 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 α (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.

AB - 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 α (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.

KW - breast cancer

KW - estrogen receptor

KW - FOXA1

KW - IL6

KW - metastasis

KW - mouse intraductal xenograft model

KW - pioneer factor

KW - STAT3

UR - http://www.scopus.com/inward/record.url?scp=85089298903&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2020.06.007

DO - 10.1016/j.ccell.2020.06.007

M3 - Article

C2 - 32679107

AN - SCOPUS:85089298903

VL - 38

SP - 412-423.e9

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 3

ER -

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

Abstract

Keywords

UN SDGs

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