Therapeutic modulation of nemo-like kinase in primary and acquired endocrine-resistant breast cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE141696 | GEO | 2021/01/11
REPOSITORIES: GEO
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Project description:Phosphoinositide-3-kinase/protein-kinaseB/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling plays an important role in breast cancer (BC). Its interaction with estrogen receptor (ER) signalling becomes more complex and inter-dependent with acquired endocrine resistance. Targeting mTOR combined with endocrine therapy has shown clinical utility, however, a negative feedback-loop exists downstream of PI3K/AKT/mTOR. Direct blockade of AKT together with endocrine therapy may improve BC treatment. AZD5363, a novel pan-AKT kinase catalytic inhibitor, was examined in a panel of ER+ BC cell lines (MCF7, HCC1428, T47D, ZR75.1) adapted to long-term-estrogen-deprivation (LTED) or tamoxifen (TamR). AZD5363 caused a dose-dependent decrease in proliferation in all cell lines tested (GI50<500nM) except HCC1428 and HCC1428-LTED. T47D-LTED and ZR75-LTED were the most sensitive of the lines (GI50~100nM). AZD5363 re-sensitised TamR cells to tamoxifen and acted synergistically with fulvestrant. AZD5363 decreased p-AKT/mTOR targets leading to a reduction in ERα-mediated transcription in a context specific manner and concomitant decrease in recruitment of ER and CREB-binding protein (CBP) to estrogen-response-elements located on the TFF1, PGR and GREB1 promoters. Furthermore, AZD5363 reduced expression of cell-cycle-regulatory proteins. Global gene expression highlighted ERBB2-ERBB3, ERK5 and IGF1 signaling pathways driven by MYC as potential feedback-loops. Combined treatment with AZD5363 and fulvestrant showed synergy in an ER+ patient derived xenograft and delayed tumour progression post-cessation of therapy. These data support the combination of AZD5363 with fulvestrant as a potential therapy for BC that is sensitive or resistant to E-deprivation or tamoxifen and that activated AKT is a determinant of response, supporting the need for clinical evaluation. Cell lines were treated in biological triplicates in the absence of estrogen with or without AZD5363 for 24hours in order to identify gene changes associated with perturbation of AKT signalling
2015-06-29 | E-GEOD-69893 | 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. 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:Phosphoinositide-3-kinase/protein-kinaseB/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling plays an important role in breast cancer (BC). Its interaction with estrogen receptor (ER) signalling becomes more complex and inter-dependent with acquired endocrine resistance. Targeting mTOR combined with endocrine therapy has shown clinical utility, however, a negative feedback-loop exists downstream of PI3K/AKT/mTOR. Direct blockade of AKT together with endocrine therapy may improve BC treatment. AZD5363, a novel pan-AKT kinase catalytic inhibitor, was examined in a panel of ER+ BC cell lines (MCF7, HCC1428, T47D, ZR75.1) adapted to long-term-estrogen-deprivation (LTED) or tamoxifen (TamR). AZD5363 caused a dose-dependent decrease in proliferation in all cell lines tested (GI50<500nM) except HCC1428 and HCC1428-LTED. T47D-LTED and ZR75-LTED were the most sensitive of the lines (GI50~100nM). AZD5363 re-sensitised TamR cells to tamoxifen and acted synergistically with fulvestrant. AZD5363 decreased p-AKT/mTOR targets leading to a reduction in ERα-mediated transcription in a context specific manner and concomitant decrease in recruitment of ER and CREB-binding protein (CBP) to estrogen-response-elements located on the TFF1, PGR and GREB1 promoters. Furthermore, AZD5363 reduced expression of cell-cycle-regulatory proteins. Global gene expression highlighted ERBB2-ERBB3, ERK5 and IGF1 signaling pathways driven by MYC as potential feedback-loops. Combined treatment with AZD5363 and fulvestrant showed synergy in an ER+ patient derived xenograft and delayed tumour progression post-cessation of therapy. These data support the combination of AZD5363 with fulvestrant as a potential therapy for BC that is sensitive or resistant to E-deprivation or tamoxifen and that activated AKT is a determinant of response, supporting the need for clinical evaluation.
2015-06-29 | GSE69893 | 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
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
Project description:Purpose: Increasing evidence suggests that epigenetic reprogramming contributes significantly to the development of endocrine therapy resistance in breast cancer. The goal of this work is to explore how the histone methyltransferase EZH2 interacts with ER signaling and drives the insensitiveness of breast cancer cells to the antagonistic effect of tamoxifen on ER activity. Therefore, we comprehensively analyzed the transcriptional program regulated by EZH2 in tamoxifen-resistant (TamR) MCF-7 cells. Methods: TamR MCF-7 cells between passage 142-144 upon were used for this assay. For mRNA-Seq, cells are transfected with scrambled control shRNAs (shCtrl) or shRNAs targeting EZH2 (shEZH2). Total RNA were extracted by TRIzol (Invitrogen) and libraries were constructed using Illumina TruSeq RNA Sample Prep Kit v2 (Cat.# RS-122-2001). Hiseq 3000 was used for sequencing.
2017-12-01 | GSE92316 | 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:We investigated gene expression changes of glucose deprived MCF-7 and T47D breast cancer cells supplemented with either 10 mM or 25 mM BHB. Glucose deprivation revealed numerous differentially expressed genes indicating an involvement of the Hippo pathway in MCF-7 cells and the NRF2-Ferroptosis axis in T47D cells. Beta-hydroxybutyrate had limited impact on breast cancer cells and differentially expressed genes were not associated with any pathways following pathway enrichment analysis.
2020-07-07 | GSE153830 | GEO
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:Aberrant activation of the forkhead protein FOXA1 is observed in advanced hormone-related cancers. However, to date, key mediators of high FOXA1 signaling remain elusive. We demonstrate that ectopic high FOXA1 (H-FOXA1) expression promotes estrogen receptor-positive (ER+) breast cancer (BC) metastasis in a xenograft mouse model. Mechanistically, H-FOXA1 reprograms ER-chromatin binding to elicit a core gene signature (CGS) and an ER-dependent secretome highly enriched in ER+ endocrine-resistant (EndoR) cells. ER+ BC MCF7-parental (P) cells treated with estrogen deprivation or estrogen, and with doxycycline (Dox)-inducible FOXA1 overexpression were used in this study. We found that a majority of the lost or retained ER binding induced by H-FOXA1 overlapped with the ER binding sites in P cells induced by estrogen vs. tamoxifen treatment. The lost ER binding sites were also significantly enriched for the ER binding under E2 vs. ED, which corresponds to 11% of the total E2-stimulated ER binding, suggesting that H-FOXA1 induces a loss of selective E2-stimulated ER binding sites. In addition, we found that the proportion of H-FOXA1-induced ER-loss regions were significantly enriched for the unique ER binding sites in P vs. tamoxifen-resistant (TamR) cells, yet no enrichment of the ER-gain regions was observed in the unique ER binding in TamR vs. P cells. Our findings uncover H-FOXA1-induced ER reprogramming driving EndoR and metastasis, possibly via a H-FOXA1/ER-dependent secretome that warrants further studies to clarify its involvement in disease progression of ER+ metastatic breast cancer.
2023-05-21 | GSE175418 | GEO