Combined targeting of G-protein-coupled receptor and EGF receptor signaling overcomes resistance to PI3K pathway inhibitors in PTEN-null triple negative breast cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA625708 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11554209.fastq.gz | Fastqsanger.gz | |||
| SRR11554210.fastq.gz | Fastqsanger.gz | |||
| SRR11554211.fastq.gz | Fastqsanger.gz | |||
| SRR11554212.fastq.gz | Fastqsanger.gz | |||
| SRR11554213.fastq.gz | Fastqsanger.gz |
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Project description:Triple-negative breast cancer (TNBC) has poorer prognosis compared to other types of breast cancers due to the lack of effective therapies and markers for patient stratification. Loss of PTEN tumor suppressor gene expression is a frequent event in TNBC, resulting in over-activation of the PI 3-kinase (PI3K) pathway and sensitivity to its inhibition. However, PI3K pathway inhibitors show limited efficacy as monotherapies on these tumors. We report a whole-genome screen to identify targets whose inhibition enhanced the effects of different PI3K pathway inhibitors on PTEN-null TNBC. This identified a signaling network that relies on both the G protein-coupled receptor for thrombin (PAR1/F2R) and downstream G protein ?? subunits and also epidermal growth factor receptor (EGFR) for the activation of the PI3K isoform p110? and AKT. Compensation mechanisms involving these two branches of the pathway could bypass PI3K blockade, but combination targeting of both EGFR and PI3K? suppressed ribosomal protein S6 phosphorylation and exerted anti-tumor activity both in vitro and in vivo, suggesting a new potential therapeutic strategy for PTEN-null TNBC.
| S-EPMC7411640 | biostudies-literature
Project description:Triple negative breast cancer (TNBC) has poorer prognosis compared to other types of breast cancers due to the lack of effective therapies and markers for patient stratification. Loss of PTEN tumor suppressor gene expression is a frequent event in TNBC, resulting in over-activation of the PI 3-Kinase (PI3K) pathway and sensitivity to its inhibition. However, PI3K pathway inhibitors show limited efficacy as monotherapies on these tumors. We report a whole genome screen to identify targets whose inhibition enhanced the effects of different PI3K pathway inhibitors on PTEN-null TNBC. This identified a signaling network that relies on both the G-protein-coupled receptor for thrombin (PAR1/F2R) and downstream G protein ?? subunits and also epidermal growth factor receptor (EGFR) for the activation of the PI3K isoform p110? and AKT. Compensation mechanisms involving these two branches of the pathway could bypass PI3K blockade, but combination targeting of both EGFR and PI3K? suppressed ribosomal protein S6 phosphorylation and exerted anti-tumor activity both in vitro and in vivo, suggesting a new potential therapeutic strategy for PTEN-null TNBC.
| S-SCDT-EMM-2020-11987 | biostudies-other
Project description:MDA-MB-468 cells were infected with a whole-genome shRNA library, treated with PI3Kbeta inhibitor (AZD8186), pan class I PI3K inhibitor (GDC0941) or AKT inhibitor (MK2206) for 6+6 days. At the end of the treatment genomic DNA was extracted. PCR amplified and shRNAs inserts were quantified by NGS.
2020-05-18 | GSE148785 | GEO
Project description:Nuclear localization of PTEN is essential for its tumor suppressive role, and loss of nuclear PTEN is more prominent than cytoplasmic PTEN in many kinds of cancers. However, nuclear PTEN-specific regulatory mechanisms were rarely reported. Based on the finding that nuclear PTEN is more unstable than cytoplasmic PTEN. Thus, 293T cells were transiently transfected with plasmid encoding Flag-tagged PTEN along with empty vector, followed by affinity purification using an anti-Flag antibody, and the bound proteins were analyzed by liquid chromatography with tandem mass spectrometry (LC−MS/MS). Here we identify that F-box only protein 22 (FBXO22) induces ubiquitylation of nuclear but not cytoplasmic PTEN at lysine 221, which is responsible for the degradation of nuclear PTEN.
2020-04-22 | PXD017983 | Pride
Project description:The transcription factor Pax5 is known to control B-cell development, but its role in mature B- cells is largely enigmatic. Here, we demonstrate by conditional mutagenesis in peripheral B- lymphocytes that B-1a, marginal zone (MZ) and germinal center B-cells as well as plasma cells are not generated upon loss of Pax5. Follicular (FO) B-cells tolerate the loss of Pax5 but have a shortened half-life. The Pax5-deficient FO B-cells fail to proliferate upon B-cell receptor or Toll- like receptor stimulation due to impaired PI3K-AKT signaling, which is caused by increased expression of PTEN, a negative regulator of the PI3K pathway. Pax5 restrains PTEN protein expression at the posttranscriptional level, likely involving Pten-targeting microRNAs. Additional PTEN loss in Pten,Pax5 double-mutant mice rescues FO B-cell numbers and the development of MZ B-cells. Hence, the posttranscriptional downregulation of PTEN expression is a dominant function of Pax5 that facilitates the differentiation and survival of mature B cells, thereby promoting humoral immunity.
2021-06-14 | GSE103260 | GEO
Project description:Previous studies have revealed that UV-stimulation of a variety of cells leads to activation of the EGF receptor, induction of Egr1, growth inhibition and apoptosis. On the other hand both Egr1 and EGF receptor activation are implicated in promoting the progression of prostate cancer. We treated M12 tumorigenic prostate epithelial cells which express little Egr1 with UV irradiation which rapidly activated the EGF receptor and elevated Egr1. Treatment with specific EGFR and ERKI/II inhibitors (PD153035 and UO126, respectively) confirmed that the upregulation of Egr1 was downstream of EGFR and ERKI/II Map kinase pathway. ChIP on chip experiments using Egr1 antibody identified 288 significantly bound promoters upon UV stimulation. Of these target genes, 40% had consensus Egr1 site in their promoters, considerably greater than that expected by chance (p < 0.005). The array binding results were validated by PCR analysis of 25 genes using DNA from conventional IP experiment. Affymetrix gene expression analysis of UV treated and control cells confirmed that a significant number of these bound promoters showed gene expression changes. Addition of siRNA to Egr1 confirmed that the gene expression changes were dependent upon Egr1 expression. Addition of EGF led to similar expression changes for nine tested genes. Proliferation and apoptosis assays confirmed that M12 cells undergo growth arrest and apoptosis following UV irradiation. Moreover, addition of EGF also promoted significant growth inhibition. These results indicate the M12 cells undergo a EGF receptor dependent apoptosis response upon UV-stimulation and that Egr1 mediates the regulation of numerous genes downstream of the EGF receptor that are associated with this response. Keywords: UV treatment analysis
2009-02-09 | GSE10585 | GEO
Project description:Sivakumar2011 - EGF Receptor Signaling Pathway
EGFR belongs to the human epidermal receptor (HER) family of receptor tyrosine kinases, which consists of four closely related receptors (EGFR (HER1, erbB1), HER2 (neu, erbB2), HER3 (erbB3), and HER4 (erbB4)) that mediate cellular signaling pathways involved in growth and proliferation in response to the binding of a variety of growth factor ligands. There are currently six known endogenous ligands for EGFR: EGF, transforming growth factor- (TGF-), amphiregulin, betacellulin, heparin-binding EGF (HB-EGF), and epiregulin.Upon ligand binding, the EGFR forms homo- or heterodimeric complexes (usually with HER2), which leads to activation of the receptor tyrosine kinase, via autophosphorylation.
References:
The EGF receptor family--multiple roles in proliferation, differentiation, and neoplasia with an emphasis on HER4.
An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors.
EGF receptor signaling: putting a new spin on eye development.
Epidermal growth factor receptor: a promising target in solid tumours.
This model is described in the article:
A systems biology approach to model neural stem cell regulation by notch, shh, wnt, and EGF signaling pathways.
Sivakumar KC, Dhanesh SB, Shobana S, James J, Mundayoor S.
Omics: a Journal of Integrative Biology. 2011; 15(10):729-737
Abstract:
The Notch, Sonic Hedgehog (Shh), Wnt, and EGF pathways have long been known to influence cell fate specification in the developing nervous system. Here we attempted to evaluate the contemporary knowledge about neural stem cell differentiation promoted by various drug-based regulations through a systems biology approach. Our model showed the phenomenon of DAPT-mediated antagonism of Enhancer of split [E(spl)] genes and enhancement of Shh target genes by a SAG agonist that were effectively demonstrated computationally and were consistent with experimental studies. However, in the case of model simulation of Wnt and EGF pathways, the model network did not supply any concurrent results with experimental data despite the fact that drugs were added at the appropriate positions. This paves insight into the potential of crosstalks between pathways considered in our study. Therefore, we manually developed a map of signaling crosstalk, which included the species connected by representatives from Notch, Shh, Wnt, and EGF pathways and highlighted the regulation of a single target gene, Hes-1, based on drug-induced simulations. These simulations provided results that matched with experimental studies. Therefore, these signaling crosstalk models complement as a tool toward the discovery of novel regulatory processes involved in neural stem cell maintenance, proliferation, and differentiation during mammalian central nervous system development. To our knowledge, this is the first report of a simple crosstalk map that highlights the differential regulation of neural stem cell differentiation and underscores the flow of positive and negative regulatory signals modulated by drugs.
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2024-09-02 | BIOMD0000000394 | BioModels
Project description:Previous studies have revealed that UV-stimulation of a variety of cells leads to activation of the EGF receptor, induction of Egr1, growth inhibition and apoptosis. On the other hand both Egr1 and EGF receptor activation are implicated in promoting the progression of prostate cancer. We treated M12 tumorigenic prostate epithelial cells which express little Egr1 with UV irradiation which rapidly activated the EGF receptor and elevated Egr1. Treatment with specific EGFR and ERKI/II inhibitors (PD153035 and UO126, respectively) confirmed that the upregulation of Egr1 was downstream of EGFR and ERKI/II Map kinase pathway. ChIP on chip experiments using Egr1 antibody identified 288 significantly bound promoters upon UV stimulation. Of these target genes, 40% had consensus Egr1 site in their promoters, considerably greater than that expected by chance (p < 0.005). The array binding results were validated by PCR analysis of 25 genes using DNA from conventional IP experiment. Affymetrix gene expression analysis of UV treated and control cells confirmed that a significant number of these bound promoters showed gene expression changes. Addition of siRNA to Egr1 confirmed that the gene expression changes were dependent upon Egr1 expression. Addition of EGF led to similar expression changes for nine tested genes. Proliferation and apoptosis assays confirmed that M12 cells undergo growth arrest and apoptosis following UV irradiation. Moreover, addition of EGF also promoted significant growth inhibition. These results indicate the M12 cells undergo a EGF receptor dependent apoptosis response upon UV-stimulation and that Egr1 mediates the regulation of numerous genes downstream of the EGF receptor that are associated with this response. Keywords: UV treatment analysis duplicated experiment for Affymetrix gene expression analysis and Chip-on-Chip analysis.
2010-05-06 | E-GEOD-10585 | biostudies-arrayexpress
Project description:Introduction Basal-like (BLCs) and epidermal growth factor receptor 2 overexpressing (HER2+) carcinomas are the subgroups of breast cancers which have the more aggressive clinical behavior. In contrast to HER2+ carcinomas, no targeted therapy is currently available for the treatment of patients with BLCs. In order to discover potential therapeutic targets, we searched for deregulated signaling pathways in human BLCs. Methods In this study, we focused on the oncogenic phosphatidylinositol 3-kinase (PI3K) pathway in twelve BLCs, and compared it to a control series of eleven hormonal receptor negative- and grade III- matched HER2+ carcinomas. The two tumor populations were first characterized by immunohistochemistry and gene expression. The PI3K pathway was then investigated by gene copy-number analysis, gene expression profiling and at a proteomic level using reverse phase protein array technology and tissue microarray. The effects of PI3K inhibition pathway on proliferation and apoptosis was further analyzed in three human basal-like cell lines. Results The PI3K pathway was found to be activated in BLCs and up-regulated compared to HER2+ tumors as shown by a significantly increased activation of the downstream targets Akt and mTOR. BLCs expressed significantly lower levels of the tumor suppressor PTEN and PTEN levels correlated negatively in a significant manner with Akt activity within that population. PTEN protein expression correlated significantly with PTEN DNA copy number and more importantly, reduced PTEN DNA copy numbers were observed specifically in BLCs. Similarly to human samples, basal-like cell lines exhibited an activation of PI3K / Akt pathway and low/lack PTEN expression. Both PI3K and mTOR inhibitors led to basal-like cell growth arrest. However, apoptosis was observed specifically after PI3K inhibition.
2008-12-03 | GSE13787 | GEO
Project description:To investigate the role of interleukin-13 (IL-13) and the epidermal growth factor (EGF) receptor pathway in controlling mucus metaplasia, normal human bronchial epithelial (NHBE) cells were cultured on air-liquid interface for 14 days and were treated with IL-13, anti-EGFR antibody or both during the final 48 h of culture. Keywords: Stimulus response
2006-11-01 | GSE4804 | GEO