Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA159579 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR488345.fastq.gz | Fastqsanger.gz | |||
| SRR488346.fastq.gz | Fastqsanger.gz | |||
| SRR488347.fastq.gz | Fastqsanger.gz | |||
| SRR488348.fastq.gz | Fastqsanger.gz | |||
| SRR488349.fastq.gz | Fastqsanger.gz |
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Project description:The estrogen receptor alpha (ERa) drives the growth of two-thirds of all breast cancers. Endocrine therapy impinges on estrogen-induced ERa activation to block tumor growth. However, half of ERa-positive breast cancers are tolerant or acquire endocrine therapy resistance. Here we demonstrate that breast cancer cells undergo genome-wide reprogramming of their chromatin landscape, defined by epigenomic maps and chromatin openness, as they acquire resistance to endocrine therapy. This reveals a role for the Notch pathway while excluding classical ERa signaling. In agreement, blocking Notch signaling, using gamma-secretase inhibitors, or targeting its downstream gene PBX1 abrogates growth of endocrine therapy-resistant breast cancer cells. Moreover Notch signaling through PBX1 directs a transcriptional program predictive of tumor outcome and endocrine therapy response. Comparing histone modifications (H3K4me2 and H3K36me3), chromatin openness (FAIRE) and PBX1 binding between endocrine therapy sensitive MCF7 and resistant MCF7-LTED cells.
2013-05-01 | E-GEOD-37323 | biostudies-arrayexpress
Project description:The estrogen receptor alpha (ERa) drives the growth of two-thirds of all breast cancers. Endocrine therapy impinges on estrogen-induced ERa activation to block tumor growth. However, half of ERa-positive breast cancers are tolerant or acquire endocrine therapy resistance. Here we demonstrate that breast cancer cells undergo genome-wide reprogramming of their chromatin landscape, defined by epigenomic maps and chromatin openness, as they acquire resistance to endocrine therapy. This reveals a role for the Notch pathway while excluding classical ERa signaling. In agreement, blocking Notch signaling, using gamma-secretase inhibitors, or targeting its downstream gene PBX1 abrogates growth of endocrine therapy-resistant breast cancer cells. Moreover Notch signaling through PBX1 directs a transcriptional program predictive of tumor outcome and endocrine therapy response.
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Project description:Phenotypic plasticity has emerged as an important mechanism of therapy resistance in cancers, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model for endocrine resistance, we show that hormone resistance is associated with enhanced phenotypic plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Our extensive omics studies, including GRO-seq on enhancer landscapes, demonstrate that the global enhancer gain/loss reprogramming driven by the differential interactions between ER-alpha and other oncogenic transcription factors (TFs), predominantly GATA3 and AP1, profoundly alters breast cancer transcriptional programs. Our functional studies in multiple biological systems support a coordinate role of GATA3 and AP1 in enhancer reprogramming that drives phenotypic plasticity to achieve endocrine resistance or cancer invasive progression. Thus, changes in TF-TF and TF-enhancer interactions can lead to genome-wide enhancer reprogramming, resulting in transcriptional dysregulations that promote plasticity and cancer therapy-resistance progression
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Project description:Cellular plasticity has emerged as an important mechanism of therapy resistance in cancers, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model for endocrine resistance, we show that hormone resistance is associated with enhanced cellular plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Our extensive omics studies including GRO-seq on enhancer landscapes demonstrate that the global enhancer gain/loss reprogramming driven by the differential interactions between ERα and other oncogenic transcription factors (TFs), predominantly GATA3 and AP1, profoundly alter breast cancer transcriptional programs. Our functional studies in various biological systems support a coordinated role of GATA3 and AP1-mediated enhancer reprogramming in driving cellular plasticity to achieve endocrine resistance or cancer invasive progression. Thus, changes in TF-TF and TF-enhancer interactions can lead to genome-wide enhancer reprogramming, resulting in transcriptional dysregulations that promote plasticity and cancer therapy-resistance progression.
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Project description:Cellular plasticity has emerged as an important mechanism of therapy resistance in cancers, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model for endocrine resistance, we show that hormone resistance is associated with enhanced cellular plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Our extensive omics studies including GRO-seq on enhancer landscapes demonstrate that the global enhancer gain/loss reprogramming driven by the differential interactions between ERα and other oncogenic transcription factors (TFs), predominantly GATA3 and AP1, profoundly alter breast cancer transcriptional programs. Our functional studies in various biological systems support a coordinated role of GATA3 and AP1-mediated enhancer reprogramming in driving cellular plasticity to achieve endocrine resistance or cancer invasive progression. Thus, changes in TF-TF and TF-enhancer interactions can lead to genome-wide enhancer reprogramming, resulting in transcriptional dysregulations that promote plasticity and cancer therapy-resistance progression.
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Project description:The vast majority of all breast cancers are driven by oestrogen receptor alpha (ERα) activation, and endocrine therapy represents the mainstay treatment for these patients. However, resistance is common and tumours progress despite years of systemic endocrine suppression. Periodic fasting enhances the efficacy of standard endocrine drugs and delay acquired resistance to them, although the underlying mechanisms remain unclear. Here, we show that fasting, in combination with endocrine therapy, induces extensive epigenetic reprogramming in hormone receptor-positive (HR+) breast cancer xenografts, with large-scale activation of glucocorticoid receptor (GR) and progesterone receptor (PR) signalling, and impairment of activator protein-1 (AP-1) family activity. GR-driven gene programs were selectively activated after fasting, and GR knockout perturbed the beneficial effects of fasting in combination with tamoxifen, in vivo. Exogenous administration of GR-ligands fully recapitulated the observed fasting-enhanced anti-oestrogen action, resulting in tumour regression. Finally, elevated progesterone and cortisol levels were detected in the blood of breast cancer patients after fasting, thus providing clinical validation of our animal findings. Our results indicate GR activation to play a pivotal role in fasting’s ability to enhance endocrine drug activity against hormone-receptor positive breast cancer and suggest that corticosteroid administration should be evaluated as an adjuvant to endocrine therapy in this condition.
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Project description:Endocrine therapy is the most used treatment for hormone receptor positive breast cancers. Despite the clear benefit of endocrine therapy for patients with ER+ breast cancer, resistance to treatment is a critical clinical issue affecting a large number of patients. While many studies have shown that genetics is an important factor in therapy resistance, recent publications have also reported that epigenetics might play a major role in the acquisition of resistance to endocrine therapies. This role is exploited both at the DNA methylation level, with activation of oncogenes and silencing of tumor suppressor genes, and at the histone modification level, with changes in chromatin accessibility. DNA methylation exerts its role in resistance both by targeting the ER itself, by inducing promoter methylation, and genome wide, by changing the methylation levels of estrogen response elements. To better understand resistance acquisition in an in vitro setting, researchers developed cellular models of endocrine therapy resistance. The prevalent strategy to identify mechanisms of resistance development and novel targets involved in the process has been to study differences between resistant and sensitive cells. Here, we performed time-resolved DNA methylation profiling of development of resistance to tamoxifen treatment and to estrogen deprivation in the T47D luminal A breast cancer cell line with the aim to identify novel drivers.
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