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IL6/STAT3 co-opts ER/FOXA1 regulatory elements to drive metastasis in breast cancer

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE126006 | GEO | 2020/07/17

REPOSITORIES: GEO

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

Project description: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.

2021-09-08 | PXD012980 | Pride

IL6/STAT3 co-opts ER/FOXA1 regulatory elements to drive metastasis in breast cancer [ATAC-Seq]

2020-07-17 | GSE150131 | GEO

IL6/STAT3 co-opts ER/FOXA1 regulatory elements to drive metastasis in breast cancer (ChIP-Seq)

2020-07-17 | GSE126004 | GEO

IL6/STAT3 co-opts ER/FOXA1 regulatory elements to drive metastasis in breast cancer (RNA-Seq)

Project description: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 a positive (ER+) breast cancer, we demonstrate that IL6 increases both primary tumor growth and distant metastases. In pre-clinical models and clinical specimens, signal transducer and activator of transcription 3 (STAT3) mediates IL6-induced activation of a metastatic gene program from enhancers shared with ER and its pioneer factor FOXA1. However, STAT3 drives transcription independent of ER and FOXA1 function from these enhancers, and the IL6/STAT3 pathway is therefore resistant to ER-targeted therapies, decoupling these two important oncogenic pathways. This demonstrates that ER/FOXA1 and IL6/STAT3 are two parallel, but functionally independent and actionable pathways controlling breast cancer progression.

2020-07-17 | GSE126003 | GEO

IL6/STAT3 co-opts ER/FOXA1 regulatory elements to drive metastasis in breast cancer

Project description:IL6/STAT3 co-opts ER/FOXA1 regulatory elements to drive metastasis in breast cancer

| PRJNA518884 | ENA

IL6/STAT3 co-opts ER/FOXA1 regulatory elements to drive metastasis in breast cancer (RNA-Seq)

Project description:IL6/STAT3 co-opts ER/FOXA1 regulatory elements to drive metastasis in breast cancer (RNA-Seq)

| PRJNA518886 | ENA

IL6/STAT3 co-opts ER/FOXA1 regulatory elements to drive metastasis in breast cancer (ChIP-Seq)

Project description:IL6/STAT3 co-opts ER/FOXA1 regulatory elements to drive metastasis in breast cancer (ChIP-Seq)

| PRJNA518885 | ENA

IL6/STAT3 co-opts ER/FOXA1 regulatory elements to drive metastasis in breast cancer [ATAC-Seq]

Project description:IL6/STAT3 co-opts ER/FOXA1 regulatory elements to drive metastasis in breast cancer [ATAC-Seq]

| PRJNA631243 | ENA

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

Project description: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.

| S-EPMC7116707 | biostudies-literature

Neuronal Inactivity Co-opts LTP Machinery to Drive Potassium Channel Splicing and Homeostatic Spike Widening.

Project description:Homeostasis of neural firing properties is important in stabilizing neuronal circuitry, but how such plasticity might depend on alternative splicing is not known. Here we report that chronic inactivity homeostatically increases action potential duration by changing alternative splicing of BK channels; this requires nuclear export of the splicing factor Nova-2. Inactivity and Nova-2 relocation were connected by a novel synapto-nuclear signaling pathway that surprisingly invoked mechanisms akin to Hebbian plasticity: Ca2+-permeable AMPA receptor upregulation, L-type Ca2+ channel activation, enhanced spine Ca2+ transients, nuclear translocation of a CaM shuttle, and nuclear CaMKIV activation. These findings not only uncover commonalities between homeostatic and Hebbian plasticity but also connect homeostatic regulation of synaptic transmission and neuronal excitability. The signaling cascade provides a full-loop mechanism for a classic autoregulatory feedback loop proposed ∼25 years ago. Each element of the loop has been implicated previously in neuropsychiatric disease.

| S-EPMC9310388 | biostudies-literature

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