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VGLL1 drives therapy resistance in estrogen receptor positive breast cancer [RNA-Seq 3]

ABSTRACT: To investigate the function of VGLL1 in breast cancer and its role in the resistance to endocrine therapies we generated stable MCF7 cells overexpressing VGLL1 using CRISPR/Cas9 Synergistic Activation Mediator (SAM) method (MCF7 ActCas9-VGLL1 cells). MCF7 ActCas9-VGLL1 cells were also cultured in the presence of fulvestrant 100nmM or 1µM to develop fulvestrant resistant cells (MCF7 ActCas9-VGLL1-FULVR) and RNA-seq was performed in the different cell lines.

ORGANISM(S): Homo sapiens

PROVIDER: GSE216528 | GEO | 2023/12/05

REPOSITORIES: GEO

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VGLL1 drives therapy resistance in estrogen receptor positive breast cancer [ChIP-Seq]

Project description:The transcriptional activity of the TEAD4 trascription factor requires co-activators. In this study we found that the expression of the TEAD coactivator VGLL1 is repressed in estrogen receptor positive breast cancer but upon resistance to endocrine threapies VGLL1 is expressed to high levels. To elucidate the importance of the coactivator VGLL1 in breast cancer cells resistant to endocrine therapies and to identify the VGLL1 target genes, we performed ChIP-seq for VGLL1 in MCF7 breast cancer cells resistant to fulvestrant (FULVR) and ChiP-seq for TEAD4 in FULVR cells and the isogenic MCF7 cells.

2023-12-05 | GSE216525 | GEO

VGLL1 drives therapy resistance in estrogen receptor positive breast cancer [RNA-Seq 1]

Project description:To investigate if the drug verteporfin can inhibit VGLL1 co-transcriptional activity in Fulvestrant resistant breast cancer cells.

2023-12-05 | GSE216526 | GEO

VGLL1 drives therapy resistance in estrogen receptor positive breast cancer [RNA-Seq 2]

Project description:To identify VGLL1 target genes we performed RNA-seq following siRNA-mediated VGLL1 downregulation in FULVR cells.

2023-12-05 | GSE216527 | GEO

Antitumor Activity of Z-endoxifen in Aromatase Inhibitor-Sensitive and Resistant Estrogen Receptor-Positive Breast Cancer

Project description:The overarching goal of this study was to explore the antitumor activity of Z-endoxifen, a tamoxifen metabolite, with first-line endocrine therapies tamoxifen and letrozole in the letrozole-sensitive MCF7 aromatase expressing model (MCF7AC1), and with second-line endocrine therapies including tamoxifen, fulvestrant, exemestane, and exemestane plus everolimus, in letrozole-resistant MCF7 model (MCF7LR) in vivo. We used microarray to identify genes that are commonly and differently reguated by Z-endoxifen and tamoxifen treatments in the letrozole-resistant MCF7LR tumors.

2020-03-13 | GSE146911 | GEO

DNA methylation of estrogen regulated enhancers defines endocrine sensitivity in breast cancer

Project description:Expression of estrogen receptor (ESR1) determines whether a breast cancer patient receives endocrine therapy as part of their adjuvant care, but does not guarantee patient response. However, the molecular factors that define endocrine response in ESR1-positive breast cancer patients remain poorly understood. Here, we characterize the DNA methylome of endocrine sensitivity and demonstrate the potential impact of differential DNA methylation on endocrine response in breast cancer. We show that DNA hypermethylation occurs predominantly at estrogen-responsive enhancers and is associated with reduced ESR1 binding and decreased gene expression of key regulators of ESR1-activity; thus providing a novel mechanism by which endocrine response is abated in ESR1-positive breast cancers. Conversely, we delineate that ESR1-responsive enhancer hypomethylation is critical in transition from normal mammary epithelial cells to endocrine responsive ESR1-positive cancer. Cumulatively these novel insights highlight the potential of ESR1-responsive enhancer methylation to both predict ESR1-positive disease and stratify ESR1-positive breast cancer patients as responders to endocrine therapy. Methylation profiling with Illumina's HumanMethylation450K array was performed on ESR1-positive hormone sensitive MCF7 cells, and three different well characterised endocrine resistant MCF7-derived cell lines; tamoxifen-resistant (TAMR), fulvestrant-resistant (FASR) and estrogen deprivation resistant (MCF7X) cells. For each cell line two biological replicates were profiled bringing the number of samples to eight.

2015-07-01 | E-GEOD-69118 | biostudies-arrayexpress

VGLL1 regulates extraembryonic lineage specification in human [CUT&TAG]

Project description:Placenta abnormality is one of the key reasons for early pregnancy loss but the regulatory mechanisms underlying placenta formation are largely unknown. Here, we applied a human naïve pluripotent stem cell (PSC) derived TE model to explore the driven regulatory machinery. We demonstrate that VGLL1 (vestigial like family member 1) is crucial for TE self-renewal and TE-specific gene expression, thus suppressing VGLL1 leads to severely impaired cell proliferation and skewed TE induction. VGLL1 exerts its function through interacting with TEAD4 (TEA domain transcription factor 4) and colocalize at target gene promoters and enhancers. Further investigation uncovers the enrichment of H3K27ac active histone marks at genomic regions occupied by VGLL1-TEAD4 complex, indicates a close association between them. Overall, our data reveals the critical function model of VGLL1-TEAD4 in human TE derivation, highlighting a potential interspecies difference between human and mouse TE induction.

2023-12-18 | GSE193618 | GEO

VGLL1 regulates extraembryonic lineage specification in human [RNA-Seq]

2023-12-18 | GSE193619 | GEO

VGLL1 regulates extraembryonic lineage specification in human [ATAC-Seq]

2023-12-18 | GSE193612 | GEO

VGLL1 regulates extraembryonic lineage specification in human [RNA-seq II]

Project description:Placenta abnormality is one of the key reasons for early pregnancy loss but the regulatory mechanisms underlying placenta formation are largely unknown. Here, we applied a human naïve pluripotent stem cell (PSC) derived TE model to explore the driven regulatory machinery. We demonstrate that VGLL1 (vestigiallikefamilymember1) is crucial for TE self-renewal and TE-specific gene expression, thus suppressing VGLL1 leads to severely impaired cell proliferation and skewed TE induction. VGLL1 exerts its function through interacting with TEAD4 (TEA domain transcription factor 4) and colocalize at target gene promoters and enhancers. Further investigation uncovers the enrichment of H3K27ac active histone marks at genomic regions occupied by VGLL1-TEAD4 complex, indicates a close association between them. Overall, our data reveals the critical function model of VGLL1-TEAD4 in human TE derivation, highlighting a potential interspecies difference between human and mouse TE induction.

2023-12-18 | GSE241813 | GEO

High CDK6 protects cells from fulvestrant-mediated apoptosis and is a predictor of resistance to fulvestrant in estrogen receptor-positive metastatic breast cancer

Project description:Purpose: Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer remains a major clinical problem. Recently, the CDK4/6 inhibitor palbociclib combined with letrozole was approved for treatment of ER+ advanced breast cancer, and other CDK4/6 inhibitors are being investigated in combination with different endocrine treatments. However, the role of CDK4/6 in endocrine resistance and their potential as predictive biomarkers of endocrine treatment response remains undefined. Experimental Design: We investigated the specific role of increased CDK6 expression in fulvestrant-resistant cells by gene knockdown and treatment with palbociclib, and evaluated the effect in cell proliferation, apoptosis and kinase activity. Furthermore, we evaluated CDK6 expression in metastatic samples from breast cancer patients treated or not with fulvestrant. Results: We found increased expression of CDK6 in two fulvestrant-resistant cell models vs. sensitive cells. Reduction of CDK6 expression impaired fulvestrant-resistant cell growth and induced apoptosis by reducing p70 ribosomal S6 kinase 2 activity. Treatment with palbociclib re-sensitized fulvestrant-resistant cells to fulvestrant through alteration of retinoblastoma phosphorylation. High CDK6 levels in metastatic samples from breast cancer patients treated with fulvestrant (N=45) correlated significantly with shorter progression-free survival (PFS) (p=0.0006), while no association was observed in patients receiving other endocrine treatments (N=41, p=0.874). Conclusions: Our results indicate that upregulation of CDK6 may be an important mechanism in overcoming fulvestrant-mediated growth inhibition in breast cancer cells. Patients with advanced ER+ breast cancer exhibiting high CDK6 expression in the metastatic lesions show shorter PFS upon fulvestrant treatment and thus may benefit from the addition of CDK4/6 inhibitors in their therapeutic regimens.

2017-02-08 | GSE74391 | GEO

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