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Global mapping of estrogen receptor and histone modifications in breast tumor samples uncovers distinct patterns for aromatase inhibitor resistance

ABSTRACT: ChIP-seq on primary breast cancer tumor samples for Era, H3K4me3, H3K27me3. Patients had a poor or good outcome after aromatase inhibitor treatment. Differential binding patterns between good and poor outcome patients were identified for each marker, predicting response to treatment

ORGANISM(S): Homo sapiens

PROVIDER: GSE40867 | GEO | 2013/12/05

SECONDARY ACCESSION(S): PRJNA175144

REPOSITORIES: GEO

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Global mapping of estrogen receptor and histone modifications in breast tumor samples uncovers distinct patterns for aromatase inhibitor resistance

Project description:ChIP-seq on primary breast cancer tumor samples for Era, H3K4me3, H3K27me3. Patients had a poor or good outcome after aromatase inhibitor treatment. Differential binding patterns between good and poor outcome patients were identified for each marker, predicting response to treatment comparing ER, H3K4me3 and H3K27me3 patterns between two breast cancer patient populations

2013-12-05 | E-GEOD-40867 | biostudies-arrayexpress

GDNF-RET signaling as a target in aromatase inhibitor resistant breast cancers

Project description:Understanding the complex molecular mechanisms underlying resistance to endocrine therapy is a major challenge in the treatment of estrogen receptor-positive (ER+) breast cancers. We have previously demonstrated that glial cell line-derived neurotrophic factor (GDNF) signaling via the receptor tyrosine kinase RET promotes estrogen independent activation of ER. Here we have addressed the relevance of GDNF-RET signaling in response to aromatase inhibitor treatment and explored the efficacy of using RET inhibitors in breast cancer models of aromatase inhibitor response and resistance. A GDNF-response gene set, identified from gene expression profiling, was demonstrated to be an independent prognostic marker of poor patient outcome and, importantly, to be predictive of poor response to aromatase inhibitor treatment and development of resistance. The relevance of these findings was validated first by demonstrating an association of RET protein expression in an independent cohort of aromatase inhibitor resistant patient samples. Second, in in vitro models, GDNF-mediated RET signaling was demonstrated to enhance the survival of aromatase inhibitor resistant cells and to increase resistance in aromatase inhibitor sensitive cells. These effects could be reversed by targeting GDNF/RET signaling with the RET selective inhibitor NVP-BBT594 thus identifying GDNF-RET signaling as a potential therapeutic target, particularly in breast cancers resistant to aromatase inhibitors.<br>MCF7 cells were E2-deprived by culturing in phenol red-free RPMI 1640 supplemented with 10% DCC for 3 days and then serum-starved overnight in the presence or absence of fulvestrant (ICI182,780) (100 nM). The following day, cells were treated with GDNF (20 ng/ml) for 0, 4, 8, 24 and 48 hours in the presence or absence of fulvestrant (ICI182,780) (100 nM).

2013-01-17 | E-MEXP-3662 | biostudies-arrayexpress

Transcription profiling of human HIV seropositive patients, CD4+ T cell decline is predicted by differential expression

Project description:Patterns of expressed genes examined in cryopreserved peripheral blood mononuclear cells (PBMCs) of seropositive persons electing to stop antiretroviral therapy in the AIDS Clinical Trials Group Study A 5170, were scrutinized to identify markers capable of predicting the likelihood of CD4+ T cell depletion after cessation of ART. Two cohorts were matched for clinical characteristics in a study of the effects of therapy interruption (TI) in ART-treated patients with immunological preservation. Disease progression was determined by CD4+ T cell count decline 24 weeks after TI.Gene Set Enrichment Analysis (GSEA) identified a set of genes in the Ras signaling pathway, associated with the downregulation of apoptosis, as significantly upregulated in the good outcome group at cessation of ART. Experiment Overall Design: There are 96 samples in this study. 24 patients with good outcome results and 24 matched patients with poor outcome results. Each patient has two time points: week0 and week 24

2008-04-04 | E-GEOD-10924 | biostudies-arrayexpress

Molecular profiling of aromatase inhibitor-treated post-menopausal breast tumors identifies immunerelated correlates of resistance

Project description:To identify in clinical breast cancer those genes and pathways most associated with resistance to aromatase inhibitors by examining the global transcriptional effects of aromatase inhibitor (AI) treatment. Analysis of gene-expression measured in core-cut biopsies at baseline and surgery from patients received 2-week’s presurgical AI revealed: i) the molecular response to AI treatment varies greatly between patients, consistent with the variable clinical benefit from AI treatment; ii) higher baseline expression of an inflammatory signature is associated with poor antiproliferative response, and should be assessed further as a novel biomarker and potential target for AI-treated patients.

2020-06-29 | GSE153470 | GEO

Comparison between matched microdissected and whole tissue breast cancer specimen

Project description:A total of 38 flash-frozen breast cancer tissues were collected from three medical centers in the Netherlands (i.e. National Cancer institute: n=19; Radboud University Medical Center: n=4; Erasmus University Medical Center: n=15). All tissues were analyzed as laser capture microdissected (LCM) and whole samples (whole tissue lysate: WTL). All gathered samples were primary estrogen receptor (ER) tumors, which were subdivided in two patient groups according to outcome to first line (i.e. recurrent disease setting) tamoxifen therapy based on time-to-progression (TTP): patients which manifested progression of disease before (i.e. TTP <=) 6 months were defined as "poor outcome", while patients which manifested progression after (i.e. TTP>) 6 months were defined as "good outcome". All patients did not receive adjuvant hormonal therapy (i.e. tamoxifen or aromatase inhibitors post-surgical resection of primary tumor). The LCM subset derives from PXD000484 (Erasmus Medical Center samples) and PXD000485 (National Cancer Institute and Radboud University Medical Center).

2016-03-31 | PXD002381 | Pride

Project description:Endocrine therapy is the preferred therapeutic strategy for estrogen receptor alpha (ERa)-positive breast cancer, but intrinsic endocrine resistance leads a significant challenge. CCCTC binding factor (CTCF)-mediated hyperactivation of ERa-associated enhancers have been recognized as important molecular mechanism leading to endocrine resistance, yet the underlying molecular mechanism of this process still remains unclear. Here, we found a critical enhancer modulator, Bromodomain PHD Finger Transcription Factor (BPTF) associated protein of 18kDa (BAP18), had a global recruitment on gene enhancer combining with CTCF. Consistently, ERa-related enhancer transactivation was highly correlated with increasing BAP18 enrichment. BAP18 interacted with SMARCA1, another nucleosome remodeling factor (NURF) complex subunit, participating modulating CTCF and ERa recruitment on enhancers. Interestingly, BAP18 globally advantaged chromatin accessibility of enhancer regions, especially the sites with CTCF binding, thereby increasing targeted enhancer-promoter looping (E-P looping) by facilitating CTCF recruitment. Our functional studies in multiple culture and aromatase inhibitor (AI)-nonresponse models reveal a critical role of BAP18 in regulating drug tolerance of breast cancer cells and patients. Collectively, our study suggested that BAP18 coordinated with CTCF in transactivating ERa-related enhancers, and exhibited a better understanding about chromatin remodeling and E-P looping mechanism of AI therapy resistance.

2022-03-16 | GSE198242 | GEO

2022-03-16 | GSE198241 | GEO

Transcriptional profiles predict treatment outcome in patients with tuberculosis and diabetes at diagnosis and at two weeks after initiation of anti-tuberculosis treatment

Project description:Globally, the anti-tuberculosis (TB) treatment success rate is approximately 85%, with treatment failure, relapse and death occurring in a significant proportion of pulmonary TB patients. Treatment success rates are lower among people with diabetes mellitus (DM). Predicting treatment failure early after diagnosis would allow early treatment adaptation and may improve global TB control. Methods Samples were collected in a longitudinal cohort study of adult TB patients with or without concomitant DM from South Africa and Indonesia to characterize whole blood transcriptional profiles before and during anti-TB treatment, using unbiased RNA-Seq and targeted gene dcRT-MLPA. Findings We report differences in whole blood transcriptome profiles between patients with a good versus poor anti-TB treatment outcome, which were observed before initiation of treatment and throughout treatment. An eight-gene and 22-gene blood transcriptional signatures distinguished patients with a good treatment outcome from patients with a poor treatment outcome at diagnosis (AUC=0·815) or two weeks (AUC=0·834) after initiation of anti-TB treatment, respectively. Importantly, high accuracy was obtained by cross-validating this signature in an external cohort (AUC=0·749). Interpretation These findings suggest that transcriptional profiles can be used as a prognostic biomarker for treatment failure and success, even in patients with concomitant DM.

2022-08-02 | GSE193979 | GEO

Expression profiling of response to first-line aromatase inhibitor therapy

Project description:Fresh-frozen primary cancer specimens of 107 breast cancer patients whose metastases were treated with first-line aromatase inhibitors were evaluated for their whole genome mRNA expression profiles.

2013-12-05 | GSE41994 | GEO

Transcription profiling of lymph node sections from patients with Stage IIIB and IIIC melanoma and poor or good prognosis

Project description:Lymph node sections from 29 patients with StageIIIB and IIIC melanoma, with divergent clinical outcome including 16 poor and 13 good prognosis patients as defined by time to tumor progression (TTP), were profiled using MWG oligonucleotide arrays,.

2008-10-21 | E-TABM-403 | biostudies-arrayexpress

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