Gene expression analysis of breast tumours from dormant and acquired resistant patients
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: PXD009328
ORGANISM(S): Homo sapiens
PROVIDER: GSE111563 | GEO | 2019/01/05
REPOSITORIES: GEO
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Project description:Sequential patient-matched samples treated with extended neoadjuvant therapy were studied. Samples were classified as pre-treatment (timepoint1, <0 days), early-on treatment (timepoint2, 0-120 days) and long-term treatment (timepoint4, >120 days).
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Project description:Understanding the molecular actions of anti-PD-1 immune checkpoint inhibitors in ER+ mouse mammary tumours is crucial to aid in understanding of how this treatment can be used in ER+ breast cancer. Here, we demonstrate that treatment of mouse mammary tumours with anti-PD-1 alone results in limited genome wide transcriptional changes. Treatment with the endocrine therapy, letrozole, results in large genome wide transcriptional changes with predominant influence on oestrogen responsive genes and genes involved in cell cycle related processes. Further, we report that treatment with a combination of both letrozole and anti-PD-1 results again produced large genome wide transcriptional changes, all of which were observed upon letrozole treatment alone.
2024-08-01 | GSE268752 | GEO
Project description:Endocrine therapies targeting the proliferative effect of 17β-estradiol (17βE2) through estrogen receptor α (ERα) are the most effective systemic treatment of ERα-positive breast cancer. However, most breast tumors initially responsive to these therapies develop resistance through a molecular mechanism that is not yet fully understood. The long-term estrogen-deprived (LTED) MCF7 cell model has been proposed to recapitulate acquired resistance to aromatase inhibitors (AIs) in postmenopausal women. To elucidate this resistance, genomic, transcriptomic and molecular data were integrated into the time course of MCF7-LTED adaptation. Dynamic and widespread genomic changes were observed, including amplification of the ESR1 locus consequently linked to an increase in ERα. Dynamic transcriptomic profiles were also observed that correlated significantly with genomic changes and were influenced by transcription factors known to be involved in acquired resistance or cell proliferation (e.g. IRF1 and E2F1, respectively) but, notably, not by canonical ERα transcriptional function. Consistently, at the molecular level, activation of growth factor signaling pathways by EGFR/ERBB/AKT and a switch from phospho-Ser118 (pS118)- to pS167-ERα were observed during MCF7-LTED adaptation. Evaluation of relevant clinical settings identified significant associations between MCF7-LTED and breast tumor transcriptome profiles that characterize ERα-negative status, early response to letrozole and recurrence after tamoxifen treatment. This study proposes a mechanism for acquired resistance to estrogen deprivation that is coordinated across biological levels and independent of canonical ERα function. LTED (long term estrogen deprived) cell line was generated from MCF-7 cells by long-term culture under estrogen deprivated conditions. And RNA samples were obtained after 3, 15, 30, 90, 120, 150 and 180 days.
2010-09-01 | E-GEOD-20361 | biostudies-arrayexpress
Project description:BACKGROUND:The risk of recurrence for endocrine-treated breast cancer patients persists for many years or even decades following surgery and apparently successful adjuvant therapy. This period of dormancy and acquired resistance is inherently difficult to investigate; previous efforts have been limited to in-vitro or in-vivo approaches. In this study, sequential tumour samples from patients receiving extended neoadjuvant aromatase inhibitor therapy were characterised as a novel clinical model. METHODS:Consecutive tumour samples from 62 patients undergoing extended (4-45?months) neoadjuvant aromatase inhibitor therapy with letrozole were subjected to transcriptomic and proteomic analysis, representing before (??0), early (13-120?days), and long-term (>?120?days) neoadjuvant aromatase inhibitor therapy with letrozole. Patients with at least a 40% initial reduction in tumour size by 4?months of treatment were included. Of these, 42 patients with no subsequent progression were classified as "dormant", and the remaining 20 patients as "acquired resistant". RESULTS:Changes in gene expression in dormant tumours begin early and become more pronounced at later time points. Therapy-induced changes in resistant tumours were common features of treatment, rather than being specific to the resistant phenotype. Comparative analysis of long-term treated dormant and resistant tumours highlighted changes in epigenetics pathways including DNA methylation and histone acetylation. The DNA methylation marks 5-methylcytosine and 5-hydroxymethylcytosine were significantly reduced in resistant tumours compared with dormant tissues after extended letrozole treatment. CONCLUSIONS:This is the first patient-matched gene expression study investigating long-term aromatase inhibitor-induced dormancy and acquired resistance in breast cancer. Dormant tumours continue to change during treatment whereas acquired resistant tumours more closely resemble their diagnostic samples. Global loss of DNA methylation was observed in resistant tumours under extended treatment. Epigenetic alterations may lead to escape from dormancy and drive acquired resistance in a subset of patients, supporting a potential role for therapy targeted at these epigenetic alterations in the management of resistance to oestrogen deprivation therapy.
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Project description:Since differential miRNA expression patterns associated with acquired AI resistance have been poorly investigated, the aim of this study was to delineate the deregulation of miRNA expression associated with letrozole response failure in a new model of letrozole resistance. For this purpose, we generated and characterized a novel cellular model of acquired resistance to letrozole (Res-Let cells) and performed microarray experiments to identify miRNAs whose expression was either deregulated between control (MCF-7aro) and resistant cells (Res-Let) or differentially expressed between the two cell lines under letrozole exposure. With the aim to select relevant miRNAs, two independent cell culture replicates were performed for each experimental condition. MCF-7aro and Res-Let cells were grown in the presence of androstenedione (AD) combined or not with letrozole. Two independent cell culture replicates for each experimental condition were used to generate total RNA. Total RNA was extracted from cell culture using a Qiagen RNA extraction kit and RNA quality was assessed using the BioAnalyzer 2100M-bM-^DM-" (Agilent Technologies). Complex probes were produced from these RNA, then hybridized to GeneChipM-BM-. miRNA 3.0 array according to the manufacturer's recommendations (Affymetrix).
2013-01-30 | E-GEOD-43766 | biostudies-arrayexpress
Project description:Resistance to endocrine therapy agents has presented a clinical obstacle in the treatment of hormone-dependent breast cancer. Our laboratory has initiated a study of microRNA regulation of signaling pathways that may result in breast cancer progression on aromatase inhibitors (AI). Microarray analysis of microRNA expression identified 115 significantly regulated microRNAs, of which 49 microRNAs were believed to be hormone-responsive. Within the AI-resistant cells, microRNAs were differentially expressed between the steroidal and non-steroidal AI-resistant lines. Also, a group of microRNAs were inversely expressed in the AI-resistant lines versus LTEDaro and tamoxifen-resistant. We focused our work on hsa-miR-128a which was hormone-responsive and up-regulated in the letrozole-resistant cell lines. Human miR-128a was shown to negatively target TGFBRI protein expression by binding to the 3âUTR region of the gene. Loss of TGFBRI resulted in compromised sensitivity to the growth inhibitory effects of TGFB in the letrozole-resistant lines. Inhibition of endogenous miR-128a resulted in re-sensitization of the letrozole-resistant lines to TGFB growth inhibitory effects. This data suggests that the hormone-responsive miR-128a can modulate TGFB signaling and survival of the letrozole-resistant cell lines. To our knowledge, this is the first study to address the role of microRNA regulation as well as TGFB signaling in AI-resistant breast cancer cell lines. We believe that in addition to estrogen-modulation of gene expression, hormone-regulated microRNAs may provide an additional level of post-transcriptional regulation of signaling pathways critically involved in breast cancer progression and AI-resistance. To look at microRNA expression profiles of breast cancer cell lines derived from MCF-7 cells that are resistant to endocrine therapy agents. MCF-7 cells that overexpress aromatase (MCF-7aro) were cultured long-term in the presence of endocrine therapy agents until cells acquired resistance. Three different aromatase inhibitors (letrozole, anastrozole or exemestane) were used, as well as the ER antagonist tamoxifen, or the hormone-free long-term estrogen deprived cells (LTED). Three replicates of the control cells (MCF-7aro) and all resistant cells were used for microarray experiments. Total of 23 samples were analyzed by microarray.
2010-05-16 | E-GEOD-17775 | biostudies-arrayexpress
Project description:Samples were taken from ER+ breast cancer patients treated with neoadjuvant endocrine therapy (letrozole) with or without CDK4/6 inhibitor (ribociclib) at the beginning of treatment, 14 days after starting treatment, or after 180 days. Nuclei were isolated and single-nucleus RNA sequencing (snRNA-seq) was performed using 10X or iCell8 technologies.
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