Alternative splicing of ALDOA determines tamoxifen resistance in breast cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE245500 | GEO | 2024/02/26
REPOSITORIES: GEO
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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:To elucidate the molecular mechanisms of tamoxifen resistance in breast cancer, we performed gene array analysis and identified 366 genes with altered expression in four unique tamoxifen resistant (TamR) cell lines vs the parental tamoxifen sensitive MCF7/S0.5 cell line. Most of these genes were funcationally linked to cell proliferation, death and control gene expression, and include FYN, PRKCA, ITPR1, DPYD, DACH1, LYN, GBP1 and PRLR. Treatment with FYN specific small interfering RNA or a SRC family kinase inhibitor reduced cell growth of TamR cell lines while exerting no significant effect on MCF7/S0.5 cells. Moreover, overexpression of FYN in parental tamoxifen-sensitive MCF7/S0.5 cells resulted in reduced sensitivity to tamoxifen, demonstrating growth and survival promoting function of FYN in MCF7 cells. FYN knockdown in TamR cells led to reduced phosphorylation of 14-3-3 and CDc 25A, suggesting that FYN, by activation of of important cell cycle-associated proteins, may overcome the anti-proliferative effects of tamoxifen. Evaluation of the subcellular localization of FYN in primary breast tumors from two cohorts of endocrine-treated ER+ breast cancer patients, one with advanced disease (N = 47) and the other with early disease (N = 76), showed that in the former, plasma membrane-associated FYN expression strongly correlated with longer progression-free survival (P<0.0002). Similarly, in early breast cancer patients, membrane-associated expression of FYN in the primary breast tumor was significantly associated with increased metastasis-free (P<0.04) and overall (P<0.004) survival independent of tumor size, grade or lymph node status. Our results indicate that FYN has an important role in tamoxifen resistance, and its subcellular localization in breast tumor cells may be an important novel biomarker of response to endocrine therapy in breast cancer.
2016-04-10 | GSE67916 | GEO
Project description:Purpose: Development of resistance to tamoxifen is an important clinical issue in the treatment of patients with breast cancer. Tamoxifen resistance may be the result of the acquisition of epigenetic regulation such as DNA methylation within breast cancer cells resulting in changed mRNA expression of genes being pivotal for estrogen dependent growth. Alternatively, tamoxifen resistance may be due to selection of preexisting resistant cells, which may exhibit cancer stem-like characteristics or a combination of the two mechanisms. Methods: To evaluate the contribution of these possible mechanisms to tamoxifen resistance, we applied modified DNA methylation-specific digital karyotyping (MMSDK) and digital gene expression (DGE) in combination with massively parallel sequencing to analyze a well-established tamoxifen resistant cell line model: MCF-7/S0.5 (tamoxifen sensitive parental cell line) and 4 high-dosage tamoxifen selected resistant offspring sublines (MCF-7/TAMR-1, MCF-7/TAMR-4, MCF-7/TAMR-7 and MCF-7/TAMR-8). MMSDK uses BssHII as mapping enzyme (DNA methylation sensitive enzyme). Both MMSDK and DGE use NlaIII and MmeI to produce 20-21 bp tag. The indexed single-end sequencing was performed by Illumina HiSeq 2000 in BGI-Shenzhen. A dynamic programming algorithm-FASTX-Toolkit implemented in Perl was used to trim the adaptor sequence. The trimmed tags were subjected to quality filtering, so that only tags with sequencing quality higher than 30 for more than 80% of the nucleotides were used for subsequent analysis. For MMSDK tag mapping, we generated a simulated reference library, i.e., BssHII reference library, by in silico enzyme digestion of the human genome (hg19, UCSC) regardless of the methylation state. This library was used as reference for subsequent mapping of the tags in the MMSDK analysis. In the DGE analysis, refMrna (hg19, UCSC) was used as reference for mapping cDNA tags. Subsequently, the BurrowsM-bM-^@M-^SWheeler Aligner (BWA) procedure for aligning the MMSDK and DGE tags to the simulated BssHII reference library and refMrna reference library, respectively, was applied. Results: MMSDK libraries using BssHII/NlaIII were generated from the parental tamoxifen sensitive subline MCF-7/S0.5 and the 4 TAMR cell lines: TAMR-1, TAMR-4, TAMR-7 and TAMR-8. The 5 indexed MMSDK libraries were sequenced in one lane and 1.38 Gb clean tag data for all 5 cell lines were obtained, with an average sequencing amount of ~270 Mb per library. On average, 59.5 % of the tags with mapping quality M-bM-^IM-% 20 were mapped back to the simulated BssHII/NlaIII reference library. DGE libraries were also generated from MCF-7/S0.5 and the 4 TAMR cell lines. The 5 indexed DGE libraries were sequenced in one lane and obtained 1.71 Gb clean tag data for all 5 cell lines with an average sequencing amount of ~340 Mb per library. On average, 40.8 % with mapping quality M-bM-^IM-% 20 were mapped back to the simulated NlaIII human transcriptome (refMrna reference library). Our present study demonstrates large differences in global gene expression and DNA methylation profiles between parental tamoxifen-sensitive cell line and 4 high-dosage tamoxifen treatment selected resistant sublines. The tamoxifen resistant cell lines exhibited globally higher methylation level than the parental cell line and an inverse relationship between gene expression and DNA methylation in the promoter regions were noticed. High expression of SOX2 and alterations of other SOX gene family members, E2F gene family members and RB-related pocket protein genes as well as highlighted stem cell pathways imply that cancer initiating cells/stem cells are involved in the resistance to tamoxifen. DNA methylation and mRNA expression profiles from tamoxifen sensitive parental cell line MCF-7/S0.5 and 4 high dosage of tamoxifen selected resistant offspring sublines (MCF-7/TAMR-1, MCF-7/TAMR-4, MCF-7/TAMR-7 and MCF-7/TAMR-8) were analyzed by MMSDK and DGE methods, respectively, in combination of massively parallel sequencing, using Illumina HiSeq 2000
2014-02-03 | E-GEOD-40665 | biostudies-arrayexpress
Project description:Alternative splicing of ALDOA determines tamoxifen resistance in breast cancer
| PRJNA1028609 | ENA
Project description:genome-wide expression profiling of MCF-7, MCF-7/TamR and CAP-treated MCF-7/TamR cell. In result, cold atmospheric plasma re-sensitizes the Tamoxifen-resistant MCF-7 (MCF-7/TamR) breast cancer cell to the drug.
2017-07-12 | GSE95208 | GEO
Project description:Quantitative phosphoproteome and transcriptome analysis of ligand-stimulated MCF-7 human breast cancer cells was performed to understand the mechanisms of tamoxifen resistance at a systems level. Phosphoproteome data revealed that wild type (WT) cells were more enriched with phospho-proteins than tamoxifen-resistant (TamR) cells after stimulation with ligands. Surprisingly, decreased phosphorylation after ligand perturbation was more common than increased phosphorylation. In particular, 17beta-estradiol (E2) induced down-regulation in WT cells at a very high rate. E2 and the ErbB ligand, heregulin (HRG) induced almost equal numbers of up-regulated phospho-proteins in WT cells. Pathway and motif activity analyses using transcriptome data additionally suggested that deregulated activation of GSK3B?(glycogen synthase kinase 3 beta) and MAPK1/3 signaling might be associated with altered activation of CREB and AP-1 transcription factors in TamR cells and this hypothesis was validated by reporter assays. An examination of clinical samples revealed that, inhibitory phosphorylation of GSK3B at serine 9 was significantly lower in tamoxifen-treated breast cancer patients that eventually had relapses, implying that activation of GSK3B may be associated with the tamoxifen resistant phenotype. Thus, the combined phosphoproteome and transcriptome dataset analyses revealed distinct signal-transcription programs in tumor cells and provided a novel molecular target to understand tamoxifen resistance. The MCF-7 human breast cancer cell line and tamoxifen-resistant MCF-7 cells were stimulated by the growth hormone heregulin (HRG) or 17beta-estradiol (E2) in the presence or absence of tamoxifen. Control was set as non-treated cells.
2010-11-03 | E-GEOD-21618 | biostudies-arrayexpress
Project description:In this study, we probed the importance of OGT activity for the survival of Tamoxifen-sensitive (TamS) and Tamoxifen-resistant (TamR) breast cancer cells. Tamoxifen is an antagonist of estrogen receptor (ERα), a transcription factor expressed in over half of all breast cancers, and the defining characteristic of the ERα-positive disease. ERα-positive breast cancers are successfully treated with Tamoxifen; however, a significant number of patients develops Tamoxifen-resistant disease. We show here that in vitro development of Tamoxifen-resistance results in acquired sensitivity to OGT small molecule inhibitor OSMI-1. Global transcriptome profiling revealed that TamS cells adapt to OSMI-1 treatment by undergoing significant chromatin compaction. In the TamR cells, however, OGT inhibition induces ERRFI1 tumor-suppressor gene expression. ERRFI1 is an endogenous inhibitor of ERBB-signaling, while activation of the ERBB-signaling is one of the best understood mechanism for Tamoxifen-resistance. We show that ERRFI1 is selectively downregulated in ERα-positive breast cancers and breast cancers driven by ERBB2, and provide data to support that this occurs through promoter methylation. Finally, we show that increased ERRFI1 expression is associated with extended survival in patients with ERα-positive tumors (p=9.2e-8). In summary, we show that Tamoxifen-resistance is associated with acquired sensitivity to OSMI-1, and propose that this is explained in part through an epigenetic activation of the tumor-suppressor ERRFI1 in response to OSMI-1 treatment.
2020-10-22 | GSE148186 | GEO
Project description:Endocrine resistance is a major obstacle in treating estrogen receptor α (ER)-positive (+) breast cancer. In order to better understand the mechanism of endocrine resistance, we established a stable tamoxifen-resistant (TamR) MCF7L cell model by culturing the parental (P) MCF7L cells in the presence of 100 nM of 4-hydroxytamoxifen (4HT) for over 6 months. To characterize the transcriptomic profiles in these cells, we performed an RNA-seq analysis.
2016-11-01 | GSE75369 | GEO
Project description:Quantitative phosphoproteome and transcriptome analysis of ligand-stimulated MCF-7 human breast cancer cells was performed to understand the mechanisms of tamoxifen resistance at a systems level. Phosphoproteome data revealed that wild type (WT) cells were more enriched with phospho-proteins than tamoxifen-resistant (TamR) cells after stimulation with ligands. Surprisingly, decreased phosphorylation after ligand perturbation was more common than increased phosphorylation. In particular, 17beta-estradiol (E2) induced down-regulation in WT cells at a very high rate. E2 and the ErbB ligand, heregulin (HRG) induced almost equal numbers of up-regulated phospho-proteins in WT cells. Pathway and motif activity analyses using transcriptome data additionally suggested that deregulated activation of GSK3B (glycogen synthase kinase 3 beta) and MAPK1/3 signaling might be associated with altered activation of CREB and AP-1 transcription factors in TamR cells and this hypothesis was validated by reporter assays. An examination of clinical samples revealed that, inhibitory phosphorylation of GSK3B at serine 9 was significantly lower in tamoxifen-treated breast cancer patients that eventually had relapses, implying that activation of GSK3B may be associated with the tamoxifen resistant phenotype. Thus, the combined phosphoproteome and transcriptome dataset analyses revealed distinct signal-transcription programs in tumor cells and provided a novel molecular target to understand tamoxifen resistance.
2010-11-03 | GSE21618 | GEO
Project description:Acquired resistance to endocrine therapy occurs with high frequency in patients with luminal breast cancer (LBC). We report here the establishment of four patient-derived xenograft models of LBC with acquired resistance in vivo to tamoxifen and estrogen deprivation. CEL files represent expresison data generated from 5 replicates (independent mice) of the following tumor models: HBCx22 (parental), HBCx22 TamR (tamoxifen-resistant), HBCx22 OvaR (ovariectomy-resistant), HBCx34 (parental), HBCx34 TamR (tamoxifen-resistant), HBCx34 OvaR (ovariectomy-resistant)
2014-07-09 | E-GEOD-55561 | biostudies-arrayexpress