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Molecular Atlas of HER2+ Breast Cancer Cells Stimulated with EGF and HRG: Temporal Insights into Mechanisms in Trastuzumab Resistance [ATAC-Seq]

ABSTRACT: Trastuzumab therapy in HER2+ breast cancer patients have mixed success owing to acquired resistance to therapy. In this study, we investigate the cellular mechanisms underlying acquired resistance using -sensitive and -resistant cancer cells (BT474 and BT474R) treated with endogenous ligands EGF and HRG, across time. Our measurements probe early receptor organization through microscopy, signaling events through multi-omic measurements and assess the cellular energetic state through mitochondrial measurements. Our integrative analyses of these multimodal measurements highlight differential mechanisms in both cell lines in response to ligands. In BT474, an active PI3K-AKT-mTORC1 signaling contributes to an active mitochondrial bioenergetic state (glycolysis and lipid metabolism) for both ligands EGF and HRG. A HIF1A mediated increase in cellular bioenergetics is also seen. In BT474R, there is a ligand-dependent activation of signaling cascades. In EGF treated BT474R, an EGFR driven IRF1/STAT1/STAT2 activation with likely impact on cellular bioenergetics is seen, whilst an AR mediated alteration of lipid metabolism is pronounced after HRG treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE237605 | GEO | 2024/02/14

REPOSITORIES: GEO

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Molecular Atlas of HER2+ Breast Cancer Cells Stimulated with EGF and HRG: Temporal Insights into Mechanisms in Trastuzumab Resistance [RNA-Seq]

Project description:Trastuzumab therapy in HER2+ breast cancer patients have mixed success owing to acquired resistance to therapy. In this study, we investigate the cellular mechanisms underlying acquired resistance using -sensitive and -resistant cancer cells (BT474 and BT474R) treated with endogenous ligands EGF and HRG, across time. Our measurements probe early receptor organization through microscopy, signaling events through multi-omic measurements and assess the cellular energetic state through mitochondrial measurements. Our integrative analyses of these multimodal measurements highlight differential mechanisms in both cell lines in response to ligands. In BT474, an active PI3K-AKT-mTORC1 signaling contributes to an active mitochondrial bioenergetic state (glycolysis and lipid metabolism) for both ligands EGF and HRG. A HIF1A mediated increase in cellular bioenergetics is also seen. In BT474R, there is a ligand-dependent activation of signaling cascades. In EGF treated BT474R, an EGFR driven IRF1/STAT1/STAT2 activation with likely impact on cellular bioenergetics is seen, whilst an AR mediated alteration of lipid metabolism is pronounced after HRG treatment.

2024-02-14 | GSE237606 | GEO

6KR-EGFR expressing MCF7 following EGF or HRG stimulation

Project description:EGF and HRG, growth factor ligands for EGFR and ErbB3/4 receptor, induce transient and sustained ERK activity associated with cellular proliferation and differentiation of MCF-7 cells, respectively. To rigorously analyze the effect of ERK signal duration for mRNA expression dynamics and its relationship with cell determination, we modified the EGF-triggered ERK signal duration by changing the EGFR activation dynamics by impairing the ubiquitination and degradation process. Mutation of the six lysine residues (6KR; K692, K713, K730, K843, K905 and K946) of the EGFR responsible for ubiquitin conjugation has shown sustained phosphorylation of the receptor (Huang et al, 2006; Goh et al, 2010). Therefore we constructed the MCF-7 cell lines that stably express 6KR EGFR (6KR), and analyzed signaling and mRNA expression dynamics in response to EGF and HRG.

2014-12-01 | GSE57547 | GEO

Transcription profiling of human MCF7 cells after EGF, HRG stimulation

Project description:Sharing common ErbB/HER receptor signaling pathway, heregulin (HRG) induces differentiation of MCF-7 breast cancer cells while epidermal growth factor (EGF) elicits proliferation. Although the cell fate led by those two ligands was totally different, the gene expression profile in early transcription was unexpectedly qualitatively similar, suggesting that the gene expression in late transcription, not early transcription, may reflect a respect of ligand specificity. In this study, based on the data from time-course microarray of all human genes, we predicted and determined a series of transcription factors which may control HRG-specific timed-late transcription and cellular differentiation of MCF-7 cells. Validation analyses showed that one of activator protein 1 (AP-1) families appeared just after c-Fos expression, another AP-1 family partner, induced expression of another transcription factor through activation of AP-1 complex. Furthermore, expression of this transcription factors caused suppression of extracellular signal-regulated kinase (ERK) phosphorylation which is sustainedly regulated by HRG-initiated ErbB signaling. Overall, our analysis indicated an importance of formation of timed-transcriptional regulatory network and its function to control upstream signaling pathway through negative feedback for cellular differentiation. Experiment Overall Design: MCF7 human breast cancer cells were stimulated by the growth hormone (epidermal growth factor (EGF) or heregulin (HRG)). Control was set as non-treated cells.

2008-10-26 | E-GEOD-13009 | biostudies-arrayexpress

MCF7 EGF, HRG stimulation

2009-05-26 | GSE13009 | GEO

Targeted inhibition of human breast cancer cell lines selected as model systems of ERBB2-positive/EGFR high breast cancer [RPPA-SKBR3]

Project description:EGFR-inhibition is required for targeted therapies of ERBB2-positive/EGFR high breast cancer. Approximately 30% of human ERBB2-positive breast tumors also express EGFR. Three targeted therapeutics (erlotinib, pertuzumab, trastuzumab) and two ligands (EGF, HRG) were analyzed in all possible combinations. Each experiment involving inhibition with targeted drugs was performed in three, and measurements without inhibitors were performed in five biological replicates. This resulted in 780 samples. Incubation with therapeutics only and dilution series of control lysated were included as controls.

2012-10-22 | E-GEOD-36326 | biostudies-arrayexpress

Targeted inhibition of human breast cancer cell lines selected as model systems of ERBB2-positive/EGFR high breast cancer [RPPA-HCC1954]

2012-10-22 | E-GEOD-36324 | biostudies-arrayexpress

MCF7 HRG stimulation

Project description:Heregulin beta-1 (HRG) is an extracellular ligand that activates mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI3K)/Akt signaling pathways through ErbB receptors. MAPK and Akt have been shown to phosphorylate the estrogen receptor (ER) at Ser-118 and Ser-167, respectively, thereby mimicking the effects of estrogenic activity such as estrogen responsive element (ERE)-dependent transcription. In the current study, integrative analysis was performed using two tiling array platforms, comprising histone H3 lysine 9 (H3K9) acetylation and RNA mapping, together with array comparative genomic hybridization (CGH) analysis in an effort to identify HRG-regulated genes in ER-positive MCF-7 breast cancer cells. Through application of various threshold settings, 333 (326 up-regulated and 7 down-regulated) HRG-regulated genes were detected. Prediction of upstream transcription factors (TFs) and pathway analysis indicated that 21% of HRG-induced gene regulation may be controlled by the MAPK cascade, while only 0.6% of the gene expression is controlled by ERE. A comparison with previously reported estrogen (E2)-regulated gene expression data revealed that only 12 common genes were identified between the 333 HRG-regulated (3.6%) and 239 E2-regulated (5.0%) gene groups. However, with respect to enriched upstream TFs, 4 common TFs were identified in the 14 HRG-regulated (28.6%) and 13 E2-regulated (30.8%) gene groups. These results indicated that while E2 and HRG may induce common TFs, the regulatory mechanisms that govern HRG- and E2-induced gene expression differ. Keywords: growth hormone response

2008-02-08 | GSE8471 | GEO

Transcription profiling of human MCF7 cells treated with ErbB receptor ligands EGF and heregulin at multiple doses and sampled at multiple time points reveals signal transduction pathways devotedly convey quantitative properties of the dose-dependent activation of ErbB receptor to early transcription

Project description:ErbB receptor ligands, epidermal growth factor (EGF) and heregulin (HRG), induce dose-dependent transient and sustained intracellular signaling, proliferation and differentiation of MCF-7 breast cancer cells, respectively. In an effort to delineate the ligand-specific cell determination mechanism, we investigated time-course gene expressions induced by EGF and HRG that induce distinct cellular phenotypes in MCF-7 cells. To analyze the effects of ligand dosage and time for the gene expression independently, we developed a statistical method for decomposing the expression profiles into the two effects. Our results indicated that signal transduction pathways devotedly convey quantitative properties of the dose-dependent activation of ErbB receptor to early transcription. The results also implied that moderate changes in the expression levels of numbers of genes, not the predominant regulation of a few specific genes, might cooperatively work at the early stage of the transcription for determining the cell fate. However, the EGF- and HRG-induced distinct signal durations resulted in the ligand-oriented biphasic induction of proteins after 20 min. The selected gene list and HRG-induced prolonged signaling suggested that transcriptional feedback to the intracellular signaling results in a graded to biphasic response in the cell determination process, and that each ErbB receptor is inextricably responsible for the control of amplitude and duration of cellular biochemical reactions. MCF-7 human breast cancer cells were incubated from 5min to 90min after administration of different concentrations of the growth hormones (epidermal growth factor (EGF) and heregulin (HRG)). Control was set as growth hormone non-treated cells. For each growth hormone, one control was used.

2007-11-01 | E-GEOD-6462 | biostudies-arrayexpress

Transcription profiling of erB2-dependent response over time to EGF and HRG stimulation of human mammary luminal epithelial cells

Project description:Our aim was to identify time-dependent changes in gene expression associated with Epidermal Growth Factor (EGF) and Hergulin B1 (HRG) stimulation of normal human mammary luminal epithelial cells (HB4a) and a derivative cell line (C3.6)overexpressing the receptor tyrosine kinase ErbB2/HER2. Serum-starved HB4a parental cells and ErbB2-overexpressing C3.6 cells were stimulated with EGF or HRG for 4 h, 18 h and 24 h or left unstimulated (0 h) prior to microarray analysis of mRNA levels of 9,932 probes, representing ~6,000 genes. Four replicates of each sample were co-hybridized to chips with a common RNA reference allowing direct comparison of gene expression across all experimental conditions: time, growth factor and cell line.

2006-08-15 | E-TABM-106 | biostudies-arrayexpress

MCF7 dose response

2006-12-09 | GSE6462 | GEO

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