IL6/STAT3 signaling hijacks ER enhancers to drive breast cancer metastasis
| Autor: | 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. |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Mice
Knockout STAT3 Transcription Factor Antineoplastic Agents Hormonal Interleukin-6 Gene Expression Profiling Estrogen Receptor alpha Breast Neoplasms Kaplan-Meier Estimate Mice SCID Xenograft Model Antitumor Assays Article Gene Expression Regulation Neoplastic Enhancer Elements Genetic Mice Inbred NOD MCF-7 Cells Animals Humans Female Neoplasm Metastasis skin and connective tissue diseases Fulvestrant Signal Transduction |
| Zdroj: | Cancer Cell |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
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