Integrated single-cell analysis reveals distinct epigenetic-regulated cancer cell states and a heterogeneity-guided core signature in tamoxifen-resistant breast cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1002300 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25528600_1.fastq.gz | Fastqsanger.gz | |||
| SRR25528600_2.fastq.gz | Fastqsanger.gz | |||
| SRR25528601_1.fastq.gz | Fastqsanger.gz | |||
| SRR25528601_2.fastq.gz | Fastqsanger.gz | |||
| SRR25528602_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 256 |
Similar Datasets
Project description:Inter- and intra-tumour heterogeneity of breast cancer might be one of the reasons that develops endocrine therapy resistance. Here, we conduct an integrated scRNA-seq and scATAC-seq analysis of ~80K breast tissue cells from two normal (NTs), three primary (PTs) and three tamoxifen-treated recurrent tumour tissues (RTs). We identify distinct cell types among breast tumour tissues and observe a striking level of cell-to-cell heterogeneity among six tumuor tissues and delineates the primary to recurrent tumour progression, underscoring the significance of these single-cell level tumour cell clusters classified from scRNA-seq data. We then define nine cancer cell states (CSs), including five PT-specific, three RT-specific and one PT-RT-shared CSs and identify a heterogeneity-guided core signature. We further identify distinct open chromatin regions and specific transcription factors (TFs) associated with cancer cell states as well as novel biological pathways that mediate their communications with the tumour microenvironment. We finally in silico characterize the core signature and in vitro functionally examine the role of one of core signature, BMP7 suggesting that it plays an oncogenic role in tamoxifen-resistant breast cancer cells, and could be a promising therapeutic target in treating endocrine resistant breast cancer. We envision this integrated single-cell epigenomic and transcriptomic measure will become a powerful approach to unravel how epigenetic factors and tumour microenvironment govern the development of tumour heterogeneity and to uncover potential therapeutic targets that circumvent heterogeneity-related failures.
2024-10-26 | GSE240112 | GEO
Project description:Tamoxifen, an antagonist to estrogen receptor (ER), is a first line drug used in breast cancer treatment. However, this therapy is complicated by the fact that a substantial number of patients exhibit either de novo or acquired resistance. To characterize the signaling mechanisms underlying the resistance to tamoxifen, we established a tamoxifen-resistant cell line by treating the MCF7 breast cancer cell line with tamoxifen for over 6 months. We showed that this cell line exhibited resistance to tamoxifen both in vitro and in vivo. In order to quantify the phosphorylation alterations associated with tamoxifen resistance, we performed SILAC-based quantitative phosphoproteomic profiling on the resistant and vehicle-treated sensitive cell lines where we identified >5,600 unique phosphopeptides. We found phosphorylation levels of 1,529 peptides were increased (>2 fold) and 409 peptides were decreased (<0.5-fold) in tamoxifen resistant cells compared to tamoxifen sensitive cells. Gene set enrichment analysis revealed that focal adhesion pathway was the top enriched signaling pathway activated in tamoxifen resistant cells. We observed hyperphosphorylation of the focal adhesion kinases FAK1 and FAK2 in the tamoxifen resistant cells. Of note, FAK2 was not only hyperphosphorylated but also transcriptionally upregulated in tamoxifen resistant cells. Suppression of FAK2 by specific siRNA knockdown could sensitize the resistant cells to the treatment of tamoxifen. We further showed that inhibiting FAK activity using the small molecule inhibitor PF562271 repressed cellular proliferation in vitro and tumor formation in vivo. More importantly, our survival analysis revealed that high expression of FAK2 significantly associated with short metastasis-free survival of ER-positive breast cancer patients treated with tamoxifen-based hormone therapy. Our studies suggest that FAK2 is a great potential target for the development of therapy for the treatment of hormone refractory breast cancers.
2016-05-25 | PXD001812 | Pride
Project description:A functional genetic screen to identify genes causing tamoxifen resistance in an estrogen-dependent human breast cancer cell model was performed. By insertion of defective retrovirus into the genome, individual genetic changes were introduced at random in ZR-75-1 cells. Subsequently, infected cells were selected for their ability to proliferate while being exposed to tamoxifen, and from these cultures stable cell lines were established. The retrovirus insertion sites were mapped enabling the identification of several candidate breast cancer anti-estrogen resistance (BCAR) genes. By cDNA transfection of estrogen-dependent cells resulting in their transformation into a tamoxifen-resistant phenotype, proof was provided for the causative role of BCAR genes.A functional genetic screen to identify genes causing tamoxifen resistance in an estrogen-dependent human breast cancer cell model was performed. By insertion of defective retrovirus into the genome, individual genetic changes were introduced at random in ZR-75-1 cells. Subsequently, infected cells were selected for their ability to proliferate while being exposed to tamoxifen, and from these cultures stable cell lines were established. The retrovirus insertion sites were mapped enabling the identification of several candidate breast cancer anti-estrogen resistance (BCAR) genes identified. By cDNA transfection of estrogen-dependent cells resulting in their transformation into a tamoxifen-resistant phenotype, proof was provided for the causative role of BCAR genes (Van Agthoven et al, Breast Cancer Res Treat DOI:10.1007/s10549-008-9969-5, 2008). To elucidate the mechanisms how these individual BCAR genes induce cell proliferation in growth-arrested ZR-75-1 cells, we assessed the gene expression patterns between the different groups of cell lines. Keywords: Expression profiling, reference design RNA was isolated from two independent cultures of 69 tamoxifen-resistant cell lines. Detailed information regarding these cell lines with respect to the viral integration sites, was described previously (Van Agthoven et al, Breast Cancer Res Treat DOI:10.1007/s10549-008-9969-5, 2008). Each sample was hybridized in duplicate/triplicate and once in a dye-swap. The mixture of cell lines used as a reference was detailed previously (Jansen et al, J Clin Oncol 23, 732, 2005).
2009-12-09 | E-GEOD-14513 | biostudies-arrayexpress
Project description:Tamoxifen Resistant (TR) gene profile from Breast cancer cell lines T47D and ZR75-1 with their oestrogen-deprieved conterparts were analysed for gene associated with TR. We used Microarray Affymetrix HU133plus 2.0 chips for gene expression of TR cell lines, normalised them against GEO data available for normal T47D (GSM70667) and ZR75-1 (GSM70668). We grew parental breast cancer cell lines in tamoxifen containing media (0.1 microM) for 6 months and labelled them tamoxifen resistant (TR). Oestrogen-Deprieved cells were grown in charcoal-stripped media for 6 months then tamoxifen (0.1 microM) was added to the media and cells maintained a further 6 months and termed Oestrogen deprieved-tamoxifen resistant (ODTR) .
2010-12-31 | E-GEOD-22664 | biostudies-arrayexpress
Project description:A functional genetic screen to identify genes causing tamoxifen resistance in an estrogen-dependent human breast cancer cell model was performed. By insertion of defective retrovirus into the genome, individual genetic changes were introduced at random in ZR-75-1 cells. Subsequently, infected cells were selected for their ability to proliferate while being exposed to tamoxifen, and from these cultures stable cell lines were established. The retrovirus insertion sites were mapped enabling the identification of several candidate breast cancer anti-estrogen resistance (BCAR) genes. By cDNA transfection of estrogen-dependent cells resulting in their transformation into a tamoxifen-resistant phenotype, proof was provided for the causative role of BCAR genes.A functional genetic screen to identify genes causing tamoxifen resistance in an estrogen-dependent human breast cancer cell model was performed. By insertion of defective retrovirus into the genome, individual genetic changes were introduced at random in ZR-75-1 cells. Subsequently, infected cells were selected for their ability to proliferate while being exposed to tamoxifen, and from these cultures stable cell lines were established. The retrovirus insertion sites were mapped enabling the identification of several candidate breast cancer anti-estrogen resistance (BCAR) genes identified. By cDNA transfection of estrogen-dependent cells resulting in their transformation into a tamoxifen-resistant phenotype, proof was provided for the causative role of BCAR genes (Van Agthoven et al, Breast Cancer Res Treat DOI:10.1007/s10549-008-9969-5, 2008). To elucidate the mechanisms how these individual BCAR genes induce cell proliferation in growth-arrested ZR-75-1 cells, we assessed the gene expression patterns between the different groups of cell lines. Keywords: Expression profiling, reference design
2009-12-10 | GSE14513 | GEO
Project description:dataset of 60 patients with ER-positive primary breast cancer and treated with tamoxifen monotherapy for 5 years. Data were generated from LCMed cancer cells. Sample_keyword: breast cancer, tamoxifen, recurrence Keywords: other
2004-06-07 | GSE1378 | GEO
Project description:Tamoxifen is an effective anti-estrogen treatment for patients with estrogen receptor-positive (ER+) breast cancer. However, about 30% of such patients receiving tamoxifen as an adjuvant therapy experience recurrence within 15 years, and most patients with advanced disease eventually develop resistance to tamoxifen. To elucidate the underlying molecular mechanisms of tamoxifen resistance, we performed a systematic analysis of miRNA-mediated gene regulation in three clinically-relevant tamoxifen-resistant human breast cancer cell lines (TamRs) compared to their parental tamoxifen-sensitive MCF-7/S0.5 cell line. Alterations in the expression of 131 miRNAs in tamoxifen-resistant vs. parental cell lines were identified, 22 of which were common to all TamRs using both sequencing and LNA-based quantitative PCR technologies. ER+ and tamoxifen sensitive breast cancer cell line (MCF-7/S0.5) and its derived tamoxifen resistant clones: TAMR-1, TAMR-4 and TAMR-8 were miRNA expression profiled in triplicates of each using Exiqon's miRCURY LNA based microRNA Ready-to-use PCR, Human panel I+II, V2.R (Exiqon, product number 203608).
2015-08-01 | E-GEOD-56411 | biostudies-arrayexpress
Project description:Tamoxifen is an effective anti-estrogen treatment for patients with estrogen receptor-positive (ER+) breast cancer. However, about 30% of such patients receiving tamoxifen as an adjuvant therapy experience recurrence within 15 years, and most patients with advanced disease eventually develop resistance to tamoxifen. To elucidate the underlying molecular mechanisms of tamoxifen resistance, we performed a systematic analysis of miRNA-mediated gene regulation in three clinically-relevant tamoxifen-resistant human breast cancer cell lines (TamRs) compared to their parental tamoxifen-sensitive MCF-7/S0.5 cell line. Alterations in the expression of 131 miRNAs in tamoxifen-resistant vs. parental cell lines were identified, 22 of which were common to all TamRs using both sequencing and LNA-based quantitative PCR technologies.
2015-08-01 | GSE56411 | GEO
Project description:dataset of 60 patients with ER-positive primary breast cancer and treated with tamoxifen monotherapy for 5 years. Data were generated from whole tissue sections of breast cancers. Sample_keyword: breast cancer, tamoxifen, recurrence Keywords: other
2004-06-07 | GSE1379 | GEO
Project description:Tamoxifen is the most widely used antiestrogen in patients with estrogen receptor (ER) positive breast cancer . However, less than half of patients benefit from tamoxifen treatment and 30-50% acquire resistance and the disease progresses. Resistance to tamoxifen is a serious problem in breast cancer therapy and major efforts are underway to find out underlying mechanisms. To find out the differential expression levels of mRNAs in tamoxifen-sensitive T47D versus tamoxifen-resistant T47D (T47DR) human breast cancer cells, T47DR (tamoxifen-resistant) cell line was established from T47D cells after the following continuous exposure to 1 μmol/L 4-Hydroxytamoxifen (H7904, Sigma, USA) for more than 6 months.Thousands of significantly different mRNA expression levels were found and analysed. Our study provides a reference data for the study of tamoxifen resistance .
2020-06-01 | GSE129544 | GEO