IL6/STAT3 co-opts ER regulatory elements to drive metastasis in breast cancer

ABSTRACT: 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.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Breast Invasive Ductal Carcinoma Cell, Cell Suspension Culture

DISEASE(S): Breast Cancer

SUBMITTER: Igor Chernukhin  

LAB HEAD: Jason Carroll, PhD FMedSci

PROVIDER: PXD012980 | Pride | 2021-09-08

REPOSITORIES: Pride