Role for the Transcriptional Activator ZRF1 in Breast Cancer Progression and Endocrine Resistance
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA413470 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6144202.fastq.gz | Fastqsanger.gz | |||
| SRR6144203.fastq.gz | Fastqsanger.gz | |||
| SRR6144204.fastq.gz | Fastqsanger.gz | |||
| SRR6144205.fastq.gz | Fastqsanger.gz | |||
| SRR6144206.fastq.gz | Fastqsanger.gz |
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Project description:RNAseq analysis upon KD of ZRF1 to prove that depletion of ZRF1 results in the acquisition of metastatic behavior and drug resistance via misregulation of cell death and cell survival related pathways in MCF7 cells.
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Project description:Breast cancer is one of the most common malignancies among women which is often treated with hormone therapy and chemotherapy. Despite the improvements in detection and treatment of breast cancer, the vast majority of breast cancer patients are diagnosed with metastatic disease either at the beginning of the disease or later during treatment. Still, the molecular mechanisms causing a therapy resistant metastatic breast cancer are still elusive. In the present study we addressed the function of the transcriptional activator ZRF1 during breast cancer progression. We provide evidence that ZRF1 plays an essential role for the early metastatic events in vitro and acts like a tumor suppressor protein during the progression of breast invasive ductal carcinoma into a more advanced stage. Hence, depletion of ZRF1 results in the acquisition of metastatic behavior by facilitating the initiation of the metastatic cascade, notably for cell adhesion, migration and invasion. Furthermore absence of ZRF1 provokes endocrine resistance via misregulation of cell death and cell survival related pathways. Taken together, we have identified ZRF1 as an important regulator of breast cancer progression that holds the potential to be explored for new treatment strategies in the future.
| S-EPMC6033359 | biostudies-literature
Project description:We profile the binding of Steroid Receptor Co-activator (SRC1) in LY2 cells, a tamoxifen-resistant cell line, in the presence and absence of tamoxifen using ChIP-sequencing technology. The development of breast cancer resistance to endocrine therapy results from an increase in cellular plasticity leading to the development of a steroid-independent tumour. The p160 steroid coactivataor protein SRC-1, through interactions with developmental proteins and other non-steroidal transcription factors, drives this tumour adaptability. Here, using discovery studies, we identify ADAM22, a non-protease member of the ADAMs family, as a direct, ER-independent target of SRC-1. Molecular, cellular and in vivo studies confirmed SRC-1 as a regulator of ADAM22. At a functional level, a role for ADAM22 in cellular migration and differentiation was observed. In vivo data from a mouse xenograft model indicated that ADAM22 expression was higher in 4-OHT-treated endocrine-resistant tumours than in tumours derived from isogenic, sensitive cells. Furthermore, in breast cancer patients, ADAM22 expression is an independent predictor of poor disease free survival. SRC-1 can function as a molecular switch which converts a steroid-responsive tumour to a steroid-resistant tumour. The ER-independent SRC-1 target ADAM22 is a potential drug target and a companion predictive biomarker in the treatment of endocrine-resistant breast cancer. Examination of SRC-1 binding in LY2 cells in the presence or absence of tamoxifen treatment. 2 replicates each.
2011-11-01 | E-GEOD-28987 | biostudies-arrayexpress
Project description:Phenotypic plasticity has emerged as an important mechanism of therapy resistance in cancers, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model for endocrine resistance, we show that hormone resistance is associated with enhanced phenotypic plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Our extensive omics studies, including GRO-seq on enhancer landscapes, demonstrate that the global enhancer gain/loss reprogramming driven by the differential interactions between ER-alpha and other oncogenic transcription factors (TFs), predominantly GATA3 and AP1, profoundly alters breast cancer transcriptional programs. Our functional studies in multiple biological systems support a coordinate role of GATA3 and AP1 in enhancer reprogramming that drives phenotypic plasticity to achieve endocrine resistance or cancer invasive progression. Thus, changes in TF-TF and TF-enhancer interactions can lead to genome-wide enhancer reprogramming, resulting in transcriptional dysregulations that promote plasticity and cancer therapy-resistance progression
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Project description:Resistance to endocrine therapy represents a major threat to patients with estrogen receptor α positive (ERα+) breast cancer. The development of resistance is mainly through activating E2F signaling. However, the mechanisms that govern E2F1 activity in these resistant cells remain poorly understood. Here, we identify Actin Gamma 1 Pseudogene 25 (AGPG) as a lncRNA whose expression is driven by epigenomic activation of enhancer in endocrine resistant breast cancer cells. High expression of AGPG is associated with poor survival of ERα+ breast cancer, especially in patients receiving endocrine therapy. Stable knockdown and overexpression of AGPG demonstrate that AGPG promotes endocrine resistance, cell cycle progression, cell proliferation in vitro and in vivo. AGPG functions by direct binding purine rich element binding protein α (PURα), a transcription factor repressing E2F1 signaling and sensitized ERα+ breast cancer cells to endocrine therapy. Via binding to the region responsible for PURα/E2F1 interaction in PURα protein, AGPG releases E2F1 from PURα, leading to activation of E2F1 signaling in ERα+ breast cancer cells. Clinically, E2F1 target genes are strongly correlated with AGPG and PURα expression. Thus, our study reveals AGPG as a promising biomarker and potential therapeutic target in breast cancer.
2023-07-12 | GSE218130 | GEO
Project description:We profile the binding of Steroid Receptor Co-activator (SRC1) in LY2 cells, a tamoxifen-resistant cell line, in the presence and absence of tamoxifen using ChIP-sequencing technology. The development of breast cancer resistance to endocrine therapy results from an increase in cellular plasticity leading to the development of a steroid-independent tumour. The p160 steroid coactivataor protein SRC-1, through interactions with developmental proteins and other non-steroidal transcription factors, drives this tumour adaptability. Here, using discovery studies, we identify ADAM22, a non-protease member of the ADAMs family, as a direct, ER-independent target of SRC-1. Molecular, cellular and in vivo studies confirmed SRC-1 as a regulator of ADAM22. At a functional level, a role for ADAM22 in cellular migration and differentiation was observed. In vivo data from a mouse xenograft model indicated that ADAM22 expression was higher in 4-OHT-treated endocrine-resistant tumours than in tumours derived from isogenic, sensitive cells. Furthermore, in breast cancer patients, ADAM22 expression is an independent predictor of poor disease free survival. SRC-1 can function as a molecular switch which converts a steroid-responsive tumour to a steroid-resistant tumour. The ER-independent SRC-1 target ADAM22 is a potential drug target and a companion predictive biomarker in the treatment of endocrine-resistant breast cancer.
2011-11-01 | GSE28987 | GEO
Project description:The estrogen receptor alpha (ERa) drives the growth of two-thirds of all breast cancers. Endocrine therapy impinges on estrogen-induced ERa activation to block tumor growth. However, half of ERa-positive breast cancers are tolerant or acquire endocrine therapy resistance. Here we demonstrate that breast cancer cells undergo genome-wide reprogramming of their chromatin landscape, defined by epigenomic maps and chromatin openness, as they acquire resistance to endocrine therapy. This reveals a role for the Notch pathway while excluding classical ERa signaling. In agreement, blocking Notch signaling, using gamma-secretase inhibitors, or targeting its downstream gene PBX1 abrogates growth of endocrine therapy-resistant breast cancer cells. Moreover Notch signaling through PBX1 directs a transcriptional program predictive of tumor outcome and endocrine therapy response. Comparing histone modifications (H3K4me2 and H3K36me3), chromatin openness (FAIRE) and PBX1 binding between endocrine therapy sensitive MCF7 and resistant MCF7-LTED cells.
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Project description:Purpose: AIB1 expression is associated with disease progression in aromastase inhibitor (AI) treated patients in breast cancer. In order to identify genes aberrantly regulated by AIB1 in AI resistance, RNA-seq was carried out in endocrine resistant LetR cells and endocrine sensitive MCF7 cells +/- AIB1 under estrogen deprivation. Methods: RNA-seq was carried out in biological triplicate in MCF7 and LetR cells comparing NT (Scramble siRNA) cells versus cells depleted of AIB1 using a SMARTpool ON-TARGETplus siRNA. RNA was extracted using Qiagen RNeasy Kit and subjected to 100bp PE sequencing using the BGISEQ 500 platform. Briefly, clean reads were mapped to reference genome using Bowtie2 and gene expression was calculated with RSEM. Differentially expressed genes (DEGs) were detected with DEseq2. With the KEGG pathway analysis, the pathway functional enrichment was performed using phyper, a function of R. Results: 61 AIB1 differentially regulated genes were identified as unique to endocrine resistant tumor cells (logfc≥1.5; Padj≤0.05).MSigDB Oncogenic signature analysis of the 61 AIB1-regulated genes revealed enrichment in growth promoting endocrine resistance pathways including LTE2, RAF, ERBB2 and MEK. Conclusion: In the endocrine resistant setting, aberrant AIB1 expression regulates the expression of genes associated with growth factor signalling.
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Project description:Combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy significantly improves the outcome of patients with advanced estrogen receptor-positive (ER+) breast cancer. However, resistance to this treatment and resultant disease progression remains a major clinical challenge. High expression of the receptor tyrosine kinase REarranged during Transfection (RET) has been associated with resistance to endocrine therapy in breast cancer, but the role of RET in CDK4/6i treatment response/resistance remains unexplored. To identify gene expression alterations associated with resistance to combined endocrine therapy and CDK4/6i, we performed global gene expression analysis and RNA sequencing of two ER+ breast cancer cell models resistant to this combined therapy.
2024-11-19 | GSE268699 | GEO
Project description:The development of breast cancer resistance to endocrine therapy results from an increase in cellular plasticity leading to the development of a steroid independent tumour. The p160 steroid coactivator protein SRC-1, through interactions with developmental proteins and other non-steroidal transcription factors drives this tumour adaptability. Here, using discovery studies we identify ADAM22, a non-protease member of the ADAMs family, as a direct target of SRC-1, independent of estrogen receptor(ER). Molecular, cellular, in vivo and clinical studies confirmed SRC-1 as a regulator of ADAM22 and established a role for ADAM22 in endocrine resistant tumour progression. ADAM22 has the potential to act as a therapeutic drug target and a companion predictive biomarker in the treatment of endocrine resistant breast cancer. 14 samples representing 4 conditions were analysed. Samples were transfected with either a siRNA targetting SRC1 or a control scrambled siRNA. Samples were subject to tamoxifen treatment or untreated.
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