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Project description:Forkhead box A1 (FOXA1) is a pioneer factor that facilitates chromatin binding and function of lineage-specific and oncogenic transcription factors. Hyperactive FOXA1 signaling due to gene amplification or overexpression has been reported in estrogen receptor-positive (ER+) endocrine-resistant metastatic breast cancer. However, the molecular mechanisms by which FOXA1 up-regulation promotes these processes and the key downstream targets of the FOXA1 oncogenic network remain elusive. Here, we demonstrate that FOXA1 overexpression in ER+ breast cancer cells drives genome-wide enhancer reprogramming to activate prometastatic transcriptional programs. Up-regulated FOXA1 employs superenhancers (SEs) to synchronize transcriptional reprogramming in endocrine-resistant breast cancer cells, reflecting an early embryonic development process. We identify the hypoxia-inducible transcription factor hypoxia-inducible factor-2? (HIF-2?) as the top high FOXA1-induced SE target, mediating the impact of high FOXA1 in activating prometastatic gene sets and pathways associated with poor clinical outcome. Using clinical ER+/HER2- metastatic breast cancer datasets, we show that the aberrant FOXA1/HIF-2? transcriptional axis is largely nonconcurrent with the ESR1 mutations, suggesting different mechanisms of endocrine resistance and treatment strategies. We further demonstrate the selective efficacy of an HIF-2? antagonist, currently in clinical trials for advanced kidney cancer and recurrent glioblastoma, in reducing the clonogenicity, migration, and invasion of endocrine-resistant breast cancer cells expressing high FOXA1. Our study has uncovered high FOXA1-induced enhancer reprogramming and HIF-2?-dependent transcriptional programs as vulnerable targets for treating endocrine-resistant and metastatic breast cancer.
| S-EPMC6936436 | biostudies-literature
Project description:Forkhead box A1 (FOXA1) is a pioneer factor that facilitates chromatin binding and function of lineage-specific and oncogenic transcription factors. Here, we have demonstrated that FOXA1 overexpression in estrogen receptor-positive breast cancer cells drives genome-wide enhancer reprogramming to activate pro-metastatic transcriptional programs. Specifically, FOXA1 overexpression generated more gained chromatin binding regions than the lost regions with decreased FOXA1 binding. Furthermore, FOXA1 overexpression led to establishment of more gained enhancers marked with increased H3K27ac and/or H3K4me1 than the lost enhancers with decreased signals of these two histone marks. In addition, these altered enhancers were highly coordinated with FOXA1-chromatin binding (cistrome) and the alteration of transcriptome due to FOXA1 overexpression, suggesting the direct engagement of high FOXA1 in enhancer reprogramming. The coordination between FOXA1 cistrome, enhancer reprogramming, and transcriptome also exists in the tamoxifen-resistant MCF7 cell model with endogenous FOXA1 gene amplification. Overall, our study supports the notion that FOXA1 overexpression promotes enhancer reprogramming in ER-positive breast cancer to activate gene expression associated with endocrine resistance and metastasis.
2019-12-18 | GSE124654 | GEO
Project description:Forkhead box A1 (FOXA1) is a pioneer factor that facilitates chromatin binding and function of lineage-specific and oncogenic transcription factors. Here, we have demonstrated that FOXA1 overexpression in estrogen receptor-positive breast cancer cells drives genome-wide enhancer reprogramming to activate pro-metastatic transcriptional programs. We have identified the hypoxia-inducible transcription factor HIF-2α as the top FOXA1-engaged super-enhancer target induced by FOXA1 overexpression, activating pro-metastatic gene signatures associated with poor breast cancer outcome. Using two different siRNA sequences, we identified 917 and 1,107 genes commonly down- and up-regulated (FDR < 0.05), respectively, upon HIF-2α knockdown in tamoxifen-resistant MCF7L cells. The enriched GO terms of the down-regulated genes were predominantly linked to tumor metastatic traits. GSEA showed that this HIF-2α-dependent gene set was significantly enriched in the transcriptomes of the TCGA ER+ breast tumors expressing high HIF-2α, but not high HIF-1α. We show the selective efficacy of a HIF-2α antagonist (PT2385), currently in clinical trial for renal cell carcinoma, in repressing migration and clonogenicity of endocrine-resistant breast cancer cells expressing high FOXA1. Our study suggests that targeting HIF-2α is a new approach blocking the aberrant transcriptional programs under high FOXA1-induced enhancer reprogramming in treating endocrine-resistant and metastatic breast cancer.
2019-12-18 | GSE124655 | GEO
Project description:FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer
| PRJNA512997 | ENA
Project description:FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer [ChIP-seq]
| PRJNA513000 | ENA
Project description:FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer [RNA-seq]
| PRJNA513001 | ENA
Project description:Resistance to aromatase inhibitors (AIs) is a major clinical problem in the treatment of estrogen receptor (ER)-positive breast cancer. In two breast cancer cell line models of AI resistance, we identified widespread DNA hyper- and hypomethylation, with enrichment for promoter hypermethylation of developmental genes. For the homeobox gene HOXC10, methylation occurred in a CpG shore, which overlapped with a functional ER binding site, causing repression of HOXC10 expression. Although short-term blockade of ER signaling caused relief of HOXC10 repression in both cell lines and breast tumors, it also resulted in concurrent recruitment of EZH2 and increased H3K27me3, ultimately transitioning to increased DNA methylation and silencing of HOXC10. Reduced HOXC10 in vitro and in xenografts resulted in decreased apoptosis and caused antiestrogen resistance. Supporting this, we used paired primary and metastatic breast cancer specimens to show that HOXC10 was reduced in tumors that recurred during AI treatment. We propose a model in which estrogen represses apoptotic and growth-inhibitory genes such as HOXC10, contributing to tumor survival, whereas AIs induce these genes to cause apoptosis and therapeutic benefit, but long-term AI treatment results in permanent repression of these genes via methylation and confers resistance. Therapies aimed at inhibiting AI-induced histone and DNA methylation may be beneficial in blocking or delaying AI resistance.
| S-EPMC4277862 | biostudies-literature
Project description:Acquired therapy resistance is a major problem for anticancer treatment, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model, we show that endocrine resistance is associated with enhanced phenotypic plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Consistently, similar gene expression changes are found in clinical breast tumours and patient-derived xenograft samples that are resistant to endocrine therapies. Mechanistically, the differential interactions between oestrogen receptor α and other oncogenic transcription factors, exemplified by GATA3 and AP1, drive global enhancer gain/loss reprogramming, profoundly altering breast cancer transcriptional programs. Our functional studies in multiple culture and xenograft models reveal a coordinated role of GATA3 and AP1 in re-organizing enhancer landscapes and regulating cancer phenotypes. Collectively, our study suggests that differential high-order assemblies of transcription factors on enhancers trigger genome-wide enhancer reprogramming, resulting in transcriptional transitions that promote tumour phenotypic plasticity and therapy resistance.
| S-EPMC7737911 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-05-21 | GSE175420 | GEO
Project description:Rationale: Cancer associated fibroblasts (CAFs) are a subpopulation of cells within the tumor microenvironment that usually promote cancer progression and metastasis. Hence it is critical to find out the driving factors and mechanisms for the development of CAFs from normal fibroblasts (NFs) in response to sustained stimulation of cancer cells. Here we perform transcriptomic and epigenomic analyses in paired NFs and CAFs associated with breast cancer metastasis to investigate the molecular mechanisms for stromal fibroblasts reprogramming. Methods: We conducted transcriptomic analyses in paired NFs and CAFs isolated from clinical specimens of breast cancer patients with metastasis. Meanwhile, genome-wide mapping of histone marks H3K4me1 and H3K27ac was also performed to characterize CAF-specific enhancer landscape. The function and mechanisms of activated JUN in stromal fibroblasts were studied using in vitro and in vivo models. Results: We have identified CAF-specific signature genes and activated enhancers, which are significantly associated with pro-metastatic programs. Among the CAF activated enhancers, FOS and JUN family of transcription factors are enriched. In line with this, we find that JUN protein is highly activated in the stroma of metastatic breast cancers. And through gain and loss-of-function studies, we demonstrate that activated JUN is necessary and sufficient to remodel enhancers and maintain the activation of CAF-specific enhancers, and thereby promotes breast cancer invasiveness in a non-cell-autonomous manner. Conclusions: Our study gets an insight into the transcriptomic features of invasive breast stroma and transcription regulatory mechanisms for stroma cell transformation, providing a proof-of-concept of stroma-targeting strategy in cancer treatment.
| S-EPMC9691365 | biostudies-literature