PacRim7 7th PacRim Meeting Poster Presentations (1) (52 abstracts)
IL6/STAT3 co-opts ER regulatory elements to drive metastasis in breast cancer
Rasmus Siersbæk 1 , Valentina Scabia 2, , Igor Chernukhin 1, , Eva Papachristou 1 , Rebecca Broome 1 , Andrew R Green 3 , Stacey Joosten 4 , Sanjeev Kumar 1, , Ruben Alvarez 1 , Sankari Nagarajan 1 , Silvia Glont 1 , Soleilmane Omarjee 1 , Sarah Aitken 1, , Kamal Kishore 1 , Emad Rakha 3 , Clive D’Santos 1 , Wilbert Zwart 4 , Alasdair Russell 1 , Cathrin Brisken 2 & Jason S Carroll 1
1Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; 2ISREC – Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole polytechnique fédérale de Lausanne (EPFL), SV2.832 Station 19, 1015 Lausanne, Switzerland; 3Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, Nottingham University and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham NG5 1PB, UK; 4Division of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Amsterdam, The Netherlands; 5Addenbrookes Hospital, Cambridge CB2 0QQ, UK. *Equal contribution.
Interleukin 6 (IL6) signaling has been associated with an aggressive and metastatic phenotype in multiple solid tumors including breast cancer, but its mechanism of action in mediating tumor progression and treatment response is not clear. By exploiting a clinically relevant intraductal xenograft model of estrogen receptor positive (ER+) breast cancer, we demonstrate that IL6 increases both primary tumor growth and distant metastases. By integrating pre-clinical models and clinical specimens, we show that signal transducer and activator of transcription 3 (STAT3) mediates IL6-induced activation of a metastatic gene program from enhancer-elements shared with ER and its pioneer factor FOXA1. Although IL6 activated STAT3 and ER/FOXA1 share cis-regulatory regions, STAT3 drives transcription independent of ER and FOXA1 function, and the IL6/STAT3 gene program is not influenced by ER-targeted therapies, decoupling these two important pathways. This demonstrates that ER/FOXA1 and IL6/STAT3 are two parallel, but independent actionable pathways controlling breast cancer progression.
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Oncology Abstracts
ISSN 2631-4657 (online)
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