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

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Authors

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

Document Type

Journal Article

Date

2020-09-14

Date Accepted

2020-06-12

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.

Citation

Cancer cell, 2020, 38 (3), pp. 412 - 423.e9

Source Title

Publisher

CELL PRESS

ISSN

1535-6108

eISSN

1878-3686

Research Team

Endocrine control mechanisms

Notes