ER reprogramming promotes a select pro-metastatic secretome in high FOXA1-expressing ER-positive endocrine-resistant and metastatic breast cancer [ChIP-seq]
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ABSTRACT:
PROVIDER: PRJNA732369 | ENA |
REPOSITORIES: ENA
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Project description:Aberrant activation of the forkhead protein FOXA1 is observed in advanced hormone-related cancers. However, to date, key mediators of high FOXA1 signaling remain elusive. We demonstrate that ectopic high FOXA1 (H-FOXA1) expression promotes estrogen receptor-positive (ER+) breast cancer (BC) metastasis in a xenograft mouse model. Mechanistically, H-FOXA1 reprograms ER-chromatin binding to elicit a core gene signature (CGS) and an ER-dependent secretome highly enriched in ER+ endocrine-resistant (EndoR) cells. ER+ BC MCF7-parental (P) cells treated with estrogen deprivation or estrogen, and with doxycycline (Dox)-inducible FOXA1 overexpression were used in this study. We found that a majority of the lost or retained ER binding induced by H-FOXA1 overlapped with the ER binding sites in P cells induced by estrogen vs. tamoxifen treatment. The lost ER binding sites were also significantly enriched for the ER binding under E2 vs. ED, which corresponds to 11% of the total E2-stimulated ER binding, suggesting that H-FOXA1 induces a loss of selective E2-stimulated ER binding sites. In addition, we found that the proportion of H-FOXA1-induced ER-loss regions were significantly enriched for the unique ER binding sites in P vs. tamoxifen-resistant (TamR) cells, yet no enrichment of the ER-gain regions was observed in the unique ER binding in TamR vs. P cells. Our findings uncover H-FOXA1-induced ER reprogramming driving EndoR and metastasis, possibly via a H-FOXA1/ER-dependent secretome that warrants further studies to clarify its involvement in disease progression of ER+ metastatic breast cancer.
2023-05-21 | GSE175418 | GEO
Project description:Aberrant activation of the forkhead protein FOXA1 is observed in advanced hormone-related cancers. However, to date, key mediators of high FOXA1 signaling remain elusive. We demonstrate that ectopic high FOXA1 (H-FOXA1) expression promotes estrogen receptor-positive (ER+) breast cancer (BC) metastasis in a xenograft mouse model. Mechanistically, H-FOXA1 reprograms ER-chromatin binding to elicit a core gene signature (CGS) highly enriched in ER+ endocrine-resistant (EndoR) cells. We identified Secretome14, a CGS subset encoding ER-dependent cancer secretory proteins, strongly predicts poor outcomes of ER+ BC and is elevated in ER+ metastases vs. primary tumors, irrespective to the ESR1 mutations. Parental (P) ER+ BC cells and their endocrine-resistant (EndoR) derivatives, and ER+ BC cells expressing doxycycline (Dox)-inducible ectopic FOXA1 were used in this study. Differential gene expression analysis was performed in EndoR vs. P cells and P cells +Dox vs. -Dox. We found that the FOXA1-CGS was highly enriched in the altered transcriptomes of two ER+ BC cell models (ZR75-1 and T47D) expressing ectopic H-FOXA1. The enriched hallmark gene sets, shared by the H-FOXA1 cell models, include “inflammatory response”, “complement”, and “interferon gamma response” for the H-FOXA1-induced, and “estrogen response early” and “estrogen response late” for the H-FOXA1-repressed genes. These findings point to the common transcriptional profile exhibiting an immune- over estrogen-responsive signature induced by H-FOXA1. In addition, we found that both the tamoxifen-resistant (TamR) and estrogen deprivation-resistant (EDR) derivatives of the 600MPE P cells were enriched for the H-FOXA1-induced CGS and FOXA1/ER-activated Secretome14. Our findings uncover H-FOXA1-induced ER reprogramming driving EndoR and metastasis, possibly via a H-FOXA1/ER-dependent secretome that warrants further studies to clarify its involvement in disease progression of ER+ metastatic BC.
2023-05-21 | GSE175401 | GEO
Project description:ER reprogramming promotes a select pro-metastatic secretome in high FOXA1-expressing ER-positive endocrine-resistant and metastatic breast cancer
| PRJNA732366 | ENA
Project description:ER reprogramming promotes a select pro-metastatic secretome in high FOXA1-expressing ER-positive endocrine-resistant and metastatic breast cancer [RNA-seq]
| PRJNA732359 | ENA
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.
2020-07-17 | GSE126004 | GEO
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.
2020-07-17 | GSE150131 | GEO
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
Project description:The primordial actions of the estrogen receptor alpha (ER) in controlling breast cancer cells proliferation rate are particularly documented. However, reintroducing ER into ER-negative cells does not reprogram their transcriptome towards an estrogen-sensitive growth phenotype. Member of the Forkhead (FKH) family of transcription factors, FOXA1 has been characterized to be essential for the appropriate binding of ER onto chromatin in MCF-7 cells. FOXA1 pioneering actions involve modulations of histone post-translational modifications (HPTMs) and local depletion in methylated CpGs. Using MDA-MB231 cells which are ER and FOXA1 negative, we aimed at determining whether the introduction of ER and FOXA1 would be sufficient to restore an estrogen-sensitive growth and to coincidently reprogram chromatin. We used ChIP-seq experiments to map ER and FOXA1 binding sites (BSs) and to profile H3K4me2 and H3K27ac marks, and surprisingly observed that FOXA1 had rather a global negative impact on ER actions, associated with an inhibition of growth and a reorientation of the transcriptome of the cells towards cell death. We demonstrate that the re-introduction of FOXA1 in these cells actually competes for the binding and pioneering actions of FOXA2, another FKH protein, on a number of ER BSs. As demonstrated for its alter ego FOXA1 in MCF-7 cells, abrogating FOXA2 expression drastically diminished ER binding onto its cognate sites, associated with a local loss of HPTMs for active chromatin.
2022-12-11 | GSE55680 | GEO
Project description:The primordial actions of the estrogen receptor alpha (ER) in controlling breast cancer cells proliferation rate are particularly documented. However, reintroducing ER into ER-negative cells does not reprogram their transcriptome towards an estrogen-sensitive growth phenotype. Member of the Forkhead (FKH) family of transcription factors, FOXA1 has been characterized to be essential for the appropriate binding of ER onto chromatin in MCF-7 cells. FOXA1 pioneering actions involve modulations of histone post-translational modifications (HPTMs) and local depletion in methylated CpGs. Using MDA-MB231 cells which are ER and FOXA1 negative, we aimed at determining whether the introduction of ER and FOXA1 would be sufficient to restore an estrogen-sensitive growth and to coincidently reprogram chromatin. We used ChIP-seq experiments to map ER and FOXA1 binding sites (BSs) and to profile H3K4me2 and H3K27ac marks, and surprisingly observed that FOXA1 had rather a global negative impact on ER actions, associated with an inhibition of growth and a reorientation of the transcriptome of the cells towards cell death. We demonstrate that the re-introduction of FOXA1 in these cells actually competes for the binding and pioneering actions of FOXA2, another FKH protein, on a number of ER BSs. As demonstrated for its alter ego FOXA1 in MCF-7 cells, abrogating FOXA2 expression drastically diminished ER binding onto its cognate sites, associated with a local loss of HPTMs for active chromatin.
2022-12-11 | GSE55740 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-05-21 | GSE175420 | GEO