Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1023282 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26351270_1.fastq.gz | Fastqsanger.gz | |||
| SRR26351270_2.fastq.gz | Fastqsanger.gz | |||
| SRR26351271_1.fastq.gz | Fastqsanger.gz | |||
| SRR26351271_2.fastq.gz | Fastqsanger.gz | |||
| SRR26351272_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 34 |
Similar Datasets
Project description:One of the greatest advances in therapy of estrogen receptor positive breast cancer has been the development of endocrine therapy. More than two thirds of primary breast tumors express estrogen receptor alpha (ERα) and their growth is mainly dependent on estrogen receptor activity. Several therapeutic approaches have thus been designed to inhibit ER activity in breast tissue. Tamoxifen, a selective ER modulator, is one of the main treatment options for premenopausal women with advanced ER positive breast cancer, and has also become well established as adjuvant therapy in the early breast cancer setting (Davies et al., 2011; Group, 1998; Jaiyesimi et al., 1995). In contrast to tamoxifen, which in other tissues such as bone and endometrium, can exert partial agonistic activity (Braithwaite et al., 2003; Fisher et al., 1994; Pietras, 2006), the selective ER downregulator, fulvestrant, is a potent ER antagonist. Binding of fulvestrant to ER inhibits receptor dimerization and nuclear uptake, prevents estrogen-response element binding and accelerates ER degradation (Dauvois et al., 1993; Dowsett et al., 2005; Fawell et al., 1990; Wakeling et al., 1991). Fulvestrant is approved for treatment of postmenopausal women with advanced breast cancer who have relapsed or progressed on first-line endocrine therapy (Howell et al., 2002; Osborne et al., 2002; Robertson et al., 2003). Estrogen deprivation by treatment with aromatase inhibitors (such as letrozole, anastrozole or exemestane) which block synthesis of estrogens is another effective therapy option in postmenopausal women (Bonneterre et al., 2000; Cuzick et al., 2010; Dowsett et al., 2010; Mouridsen et al., 2001; Nabholtz et al., 2000). The large majority of patients with ER+ breast cancer experience an initial response to endocrine therapy, however, in many of these patients, the disease subsequently progresses and eventually anti-estrogen therapy ceases to have effect. Biomarkers predicting response to estrogen deprivation and new alternative treatments targeting the pathways supporting estrogen independent growth are therefore urgently needed (Patani and Martin, 2014; Patani et al., 2013). In order to understand how tumors respond to withdrawal of their main growth signal, a comparison of molecular features of tumor before and during endocrine therapy is necessary, and the fate of individual cancer cell sub-clones should be monitored. Since studies of cellular dynamics are very difficult to perform with clinical material, we made use of a patient derived, estrogen dependent, orthotopically growing luminal-like primary breast cancer xenograft model (PDX) (Bergamaschi et al., 2009; Huuse et al., 2012). This PDX model is a representative model for luminal breast cancers as the molecular characteristics, cellular heterogeneity and estrogen dependency of the primary tumor are retained over many passages. Functionally different subpopulations of cancer cells were previously defined by expression of the markers CD24 and SSEA-4 in this model (Skrbo et al., 2014), and it is therefore a suitable model for comparison of cellular and molecular effects of estrogen deprivation and ER-signaling inhibition. In this study, a quantitative MS-based proteomic analysis using SILAC and a label-free approach were performed, aiming to map changes in protein expression induced by endocrine therapy. Inhibition of ER-signaling seemed to induce CD24 and SSEA-4 expression on residual tumor cells. Proteomic analysis revealed overexpression of enzymes involved in TCA cycle, oxidative phosphorylation and fatty acid beta-oxidation following endocrine treatment when compared to untreated tumors. These results indicated possible reprogramming of cell metabolism and utilization of aerobic respiration, i.e. oxidative phosphorylation, in response to endocrine therapy.
2022-02-28 | PXD002352 | Pride
Project description:*** This submission includes RNA data, with DNA files available under a different accession number*** Purpose: Endocrine therapy resistance remains the greatest challenge for treating hormone receptor positive breast cancer patients. We aim to identify molecular mechanisms underlying endocrine therapy resistance through in-depth genomic analysis of patient samples. Experimental Design: We collected tumors from 35 estrogen receptor positive breast cancer patients receiving endocrine therapy, of which 3 patients had intrinsic resistance and 19 patients developed acquired resistance. For each patient, multiple tumor specimens were collected during the course of treatment. We performed DNA whole exome sequencing and RNA sequencing on all tumor samples. DNA mutations, copy number alterations and RNA gene expression data were analyzed through supervised analyses comparing paired sensitive and resistant tumor samples to identify molecular features related to endocrine therapy resistance. Results: We identified mutations enriched in resistant tumors including ESR1 and GATA3. ESR1 D538G variant confers endocrine therapy resistance while E380Q variant confers hypersensitivity. We demonstrate that resistant tumors had distinct gene expression profiles and elevated signaling pathways including ER, HER2, GATA3, AKT, RAS and p63 signaling. Integrated analysis for individual patient highlighted the heterogeneity of endocrine therapy resistance mechanisms. Conclusions: Our results suggest that mechanisms underlying endocrine therapy resistance are highly heterogeneous with diverse changes in genomic and transcriptomic levels.
2022-09-01 | E-MTAB-9917 | biostudies-arrayexpress
Project description:Recent analyses have identified heterogeneity in estrogen receptor (ER)-positive breast cancer. There are so-called luminal A and luminal B subtypes, and the characteristics, such as response to endocrine therapy and chemotherapy and prognosis, are different in these two subtypes of breast cancer. In this study, expression profiles of microRNAs (miRNAs) and mRNAs in ER-positive breast cancer tissues were compared between highly and incompletely endocrine responsive tumors by miRNA and mRNA microarrays. Unsupervised hierarchical clustering analyses revealed distinct expression patterns of miRNAs and mRNAs in these two groups. We identified one miRNA that was downregulated in highly endocrine responsive tumors and 8 miRNAs that were downregulated in incompletely endocrine responsive tumors, and target genes of these miRNAs were predicted using TargetScan and MiRanda. Protein expression patterns of the predicted target genes and the genes that were identified by mRNA expression profiling were analyzed in ER-positive breast cancer samples by immunohistochemistry. We identified a novel protein that might be associated with characteristics of ER-positive breast cancer.
2013-03-04 | GSE38278 | GEO
Project description:Recent analyses have identified heterogeneity in estrogen receptor (ER)-positive breast cancer. There are so-called luminal A and luminal B subtypes, and the characteristics, such as response to endocrine therapy and chemotherapy and prognosis, are different in these two subtypes of breast cancer. In this study, expression profiles of microRNAs (miRNAs) and mRNAs in ER-positive breast cancer tissues were compared between highly and incompletely endocrine responsive tumors by miRNA and mRNA microarrays. Unsupervised hierarchical clustering analyses revealed distinct expression patterns of miRNAs and mRNAs in these two groups. We identified one miRNA that was downregulated in highly endocrine responsive tumors and 8 miRNAs that were downregulated in incompletely endocrine responsive tumors, and target genes of these miRNAs were predicted using TargetScan and MiRanda. Protein expression patterns of the predicted target genes and the genes that were identified by mRNA expression profiling were analyzed in ER-positive breast cancer samples by immunohistochemistry. We identified a novel protein that might be associated with characteristics of ER-positive breast cancer.
2013-03-04 | GSE38279 | GEO
Project description:Combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy significantly improves the outcome of patients with advanced estrogen receptor-positive (ER+) breast cancer. However, resistance to this treatment and resultant disease progression remains a major clinical challenge. High expression of the receptor tyrosine kinase REarranged during Transfection (RET) has been associated with resistance to endocrine therapy in breast cancer, but the role of RET in CDK4/6i treatment response/resistance remains unexplored. To identify gene expression alterations associated with resistance to combined endocrine therapy and CDK4/6i, we performed global gene expression analysis and RNA sequencing of two ER+ breast cancer cell models resistant to this combined therapy.
2024-11-19 | GSE268699 | GEO
Project description:Neurofibromin/NF1-depletion (NF1low) is associated with endocrine therapy resistance in approximately 20% of ER+/HER2– early-stage breast cancer but specific treatments for NF1low tumors are not established. Proteogenomic analyses on ER+/HER2– breast cancer demonstrated that NF1low tumors exhibit elevated CDK4/6 activity. NF1-silencing in cell lines promoted ER recruitment to CCND1, thus increasing cyclin-D1 levels. Additionally, RAF is demonstrated to directly phosphorylate the CDK4 activation-loop (pT172) thus providing a direct connection between NF1 loss and an increase in CDK4 activity. Consequently, NF1low cancer cells are differentially sensitive to a fulvestrant plus CDK4/6 inhibitor (CDK4/6i) combination, with cell-death induction in vitro, and durable tumor regressions in ER+ NF1low PDX models in vivo. Furthermore, NF1low ER+/HER2– tumors treated neoadjuvantly with 4 weeks of anastrozole exhibited a minimal reduction of a multigene mRNA proliferation score vs NF1high tumors but exhibited marked sensitivity to the subsequent addition of palbociclib. In conclusion, dual ER and downstream RAF activation following NF1-loss drives endocrine therapy resistance and CDK4/6i sensitivity in NF1low ER+ breast cancer. NF1 status should therefore be prioritized for biomarker investigations in adjuvant CDK4/6i trials to determine whether the NF1low status identifies a particularly sensitive subset where CDK4/6i therapy is critical.
2025-05-27 | GSE273881 | GEO
Project description:Retrospective series of primary breast cancer patients who received surgery between 1989 and 1992. Patients received adjuvant chemotherapy and/or adjuvant hormone therapy, or no adjuvant treatment. Tamoxifen was used as endocrine therapy for 5 years in ER+ BC patients. Patients who were <50 years of age, with lymph node positive tumors, or ER– and/or >3 cm in diameter, received adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) for six cycles, in a thrice weekly intravenous regimen. Patients >50 years of age with ER–, lymph node–positive tumors also received CMF. Retrospective clinical study to identify breast cancer prognostic markers and associated pathways. 210 early primary breast cancers were considered who had complete 10-years follow-up, clinical and demographics information. miRNA profiling data.
2011-07-08 | E-GEOD-22216 | biostudies-arrayexpress
Project description:Retrospective series of primary breast cancer patients who received surgery between 1989 and 1992. Patients received adjuvant chemotherapy and/or adjuvant hormone therapy, or no adjuvant treatment. Tamoxifen was used as endocrine therapy for 5 years in ER+ BC patients. Patients who were <50 years of age, with lymph node positive tumors, or ER– and/or >3 cm in diameter, received adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) for six cycles, in a thrice weekly intravenous regimen. Patients >50 years of age with ER–, lymph node–positive tumors also received CMF. Retrospective clinical study to identify breast cancer prognostic markers and associated pathways. 216 early primary breast cancers were considered who had complete 10-years follow-up, clinical and demographics information. mRNA profiling data.
2011-07-08 | E-GEOD-22219 | biostudies-arrayexpress
Project description:MCM3 is one of several genes whose expression profile is markedly altered in tamoxifen-resistant breast cancer cell lines. We observed that increased MCM3 expression is associated with tamoxifen resistance. Knockdown of MCM3 resulted in increased susceptibility of tamoxifen-resistant breast cancer cell lines. Moreover, MCM3 expression is significantly associated with clinical outcome of endocrine treated receptor positive breast cancer. To understand the effect of MCM3 on the mechanism of endocrine resistance, we performed gene expression array on tamoxifen-resistant breast cancer cell lines. Here we show that MCM3 knockdown affects the expression of hundreds of genes. Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer is a major clinical problem with poorly understood mechanisms. There is an unmet need for prognostic and predictive biomarkers to allow appropriate therapeutic targeting. We evaluated the mechanism by which minichromosome maintenance protein 3 (MCM3) influences endocrine resistance and its predictive/prognostic potential in ER+ breast cancer. We discovered that ER+ breast cancer cells survive tamoxifen and letrozole treatments through upregulation of minichromosome maintenance proteins (MCMs), including MCM3, which are key molecules in cell cycle and DNA replication. Lowering MCM3 expression in endocrine-resistant cells restored drug sensitivity and altered phosphorylation of cell cycle regulators, including p53(Ser315,33), CHK1(Ser317) and cdc25b(Ser323), suggesting that the interaction of MCM3 with cell cycle proteins is an important mechanism of overcoming replicative stress and anti-proliferative effects of endocrine treatments. Evaluation of MCM3 levels in primary tumors from four independent cohorts of breast cancer patients receiving adjuvant tamoxifen mono-therapy or no adjuvant treatment, including the Stockholm tamoxifen (STO-3) trial, showed MCM3 to be an independent prognostic adding information beyond Ki67. In addition, MCM3 was shown to be a predictive marker of response to endocrine treatment. Our study reveals a coordinated signaling network centered around MCM3 that limits response to endocrine therapy in ER+ breast cancer and identifies MCM3 as a clinically useful prognostic and predictive biomarker that allows personalized treatment of ER+ breast cancer patients.
2020-11-17 | GSE148878 | GEO
Project description:Here we characterise the response of models of ER-positive breast cancer to treatment with the small molecule MDM2 inhibitor NVP-CGM097, a dihydroisoquinolinone derivative currently evaluated in a phase I clinical trial. We show that NVP-CGM097 reduces tumour cell viability of in vitro and in vivo models of endocrine sensitive, endocrine resistant and palbociclib (CDK4/6 inhibitor) resistant p53 wildtype (p53wt) ER-positive breast cancer. NVP-CGM097 synergises with both fulvestrant and palbociclib in models of therapy resistance. Importantly, we identify the key mechanisms of the synergistic interactions between NVP-CGM097 and endocrine therapy, which occurs through the inhibition of E2F Targets and G2M Checkpoint signalling and induction of senescence, rather than depending upon upregulation of p53 dependent apoptotic pathways. Moreover, we find these same pathways are synergistically targeted during the combination treatment of ER positive breast cancer models with NVP-CGM097 and palbociclib. This indicates the genuine potential of MDM2 inhibition as therapy in advanced ER-positive breast cancer as combination endocrine therapy and CDK4/6 inhibitor treatment becomes embedded as standard of care.
2020-04-01 | GSE140758 | GEO