Regulation of KMT2D by PI(3)K/AKT signalling orchestrates oestrogen receptor mediated transcriptional activation in breast cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE84594 | GEO | 2017/03/01
SECONDARY ACCESSION(S): PRJNA330537
REPOSITORIES: GEO
Similar Datasets
Project description:We aim to elucidate the mechanisms of how PI3K inhibition is promoting estrogen receptor (ER) activation and ER dependency in breast cancer.
2017-04-01 | GSE95366 | GEO
Project description:We aim to elucidate the mechanisms of how PI3K inhibition is promoting oestrogen receptor (ER) activation and ER dependency in breast cancer.
2017-03-01 | GSE84593 | GEO
Project description:We aim to elucidate the mechanisms of how PI3K inhibition is promoting oestrogen receptor (ER) activation and ER dependency in breast cancer.
2017-03-01 | GSE84515 | GEO
Project description:Regulation of KMT2D by PI(3)K/AKT signalling orchestrates oestrogen receptor mediated transcriptional activation in breast cancer
| PRJNA330537 | ENA
Project description:Oestrogen receptor-negative (ER-) breast cancer is intrinsically sensitive to chemotherapy. However, tumour response is often incomplete, and relapse occurs with high frequency. The aim of this work was to analyse the molecular characteristics of residual tumours and early response to chemotherapy in patient-derived xenografts (PDXs) of breast cancer.Gene and protein expression profiles were analysed in a panel of ER- breast cancer PDXs before and after chemotherapy treatment. Tumour and stromal interferon-gamma expression was measured in xenografts lysates by human and mouse cytokine arrays, respectively.The analysis of residual tumour cells in chemo-responder PDX revealed a strong overexpression of IFN-inducible genes, induced early after AC treatment and associated with increased STAT1 phosphorylation, DNA-damage and apoptosis. No increase in IFN-inducible gene expression was observed in chemo-resistant PDXs upon chemotherapy. Overexpression of IFN-related genes was associated with human IFN-? secretion by tumour cells.Treatment-induced activation of the IFN/STAT1 pathway in tumour cells is associated with chemotherapy response in ER- breast cancer. Further validations in prospective clinical trials will aim to evaluate the usefulness of this signature to assist therapeutic strategies in the clinical setting.
| S-EPMC4815803 | biostudies-literature
Project description:IntroductionTamoxifen is effective for endocrine treatment of oestrogen receptor-positive breast cancers but ultimately fails due to the development of resistance. A functional screen in human breast cancer cells identified two BCAR genes causing oestrogen-independent proliferation. The BCAR1 and BCAR3 genes both encode components of intracellular signal transduction, but their direct effect on breast cancer cell proliferation is not known. The aim of this study was to investigate the growth control mediated by these BCAR genes by gene expression profiling.MethodsWe have measured the expression changes induced by overexpression of the BCAR1 or BCAR3 gene in ZR-75-1 cells and have made direct comparisons with the expression changes after cell stimulation with oestrogen or epidermal growth factor (EGF). A comparison with published gene expression data of cell models and breast tumours is made.ResultsRelatively few changes in gene expression were detected in the BCAR-transfected cells, in comparison with the extensive and distinct differences in gene expression induced by oestrogen or EGF. Both BCAR1 and BCAR3 regulate discrete sets of genes in these ZR-75-1-derived cells, indicating that the proliferation signalling proceeds along distinct pathways. Oestrogen-regulated genes in our cell model showed general concordance with reported data of cell models and gene expression association with oestrogen receptor status of breast tumours.ConclusionsThe direct comparison of the expression profiles of BCAR transfectants and oestrogen or EGF-stimulated cells strongly suggests that anti-oestrogen-resistant cell proliferation is not caused by alternative activation of the oestrogen receptor or by the epidermal growth factor receptor signalling pathway.
| S-EPMC1064102 | biostudies-literature
Project description:IntroductionOestrogens can mediate some of their cell survival properties through a nongenomic mechanism that involves the mitogen-activated protein kinase (MAPK) pathway. The mechanism of this rapid signalling and its dependence on a membrane bound oestrogen receptor (ER), however, remains controversial. The role of G-protein-coupled receptor and epidermal growth factor (EGF) receptor in an ER-independent signalling pathway modulated by oestrogen was investigated.MethodsER-positive and ER-negative breast cancer cell lines (MCF-7 and SKBR3) and primary breast cancer cell cultures were used in this study. Cell proliferation was assessed using standard MTT assays. Protein and cAMP levels were detected by Western blotting and ELISA, respectively. Antigen localization was performed by immunocytochemistry, immunohistochemistry and immunofluorescence. Protein knockdown was achieved using small interfering RNA technologies.ResultsEGF and oestrogen, alone and in combination, induced cell proliferation and phosphorylation of MAPK proteins Raf and ERK (extracellular signal regulated kinase)1/2 in both ER-negative SKBR3 and ER-positive MCF-7 human breast cancer cell lines. Increased Raf phosphorylation was also observed in primary human breast cultures derived from ER-positive and ER-negative breast tumours. Oestrogen induced an increase in intracellular cAMP in ER-negative SKBR3 human breast cancer cells. Oestrogen-mediated cell growth and phosphorylation of MAPK was modified by the EGF receptor antagonist AG1478, the G-protein antagonist pertussis toxin, and the angiotensin II receptor antagonist saralasin. Knockdown of angiotensin II type 1 receptor (AT1) protein expression with small interfering RNA attenuated oestrogen-induced Raf phosphorylation in ER-negative cells. AT1 receptor was found to be expressed in the cell membrane of breast tumour epithelial cells.ConclusionThese findings provide evidence that, in breast cancer cells, oestrogen can signal through AT1 to activate early cell survival mechanisms in an ER-independent manner.
| S-EPMC1557727 | biostudies-literature
Project description:PurposeOestrogen receptor β is believed to exert a cardioprotective effect against ischaemic injury. Nonetheless, the mechanism underlying its protective action remains to be fully elucidated. Recently, increased attention has been focused on Notch1 signalling for ameliorating cardiac ischaemic injury. Here, we hypothesised that oestrogen receptor β activation attenuates myocardial infarction (MI)-induced cardiac damage by modulating the Notch1 signalling pathway.MethodsMale C57BL/6 mice were used to establish an MI model through the ligation of the anterior descending branch of the left coronary artery. Two chemical drugs, 2,3-Bis(4-hydroxyphenyl)-propionitrile (DPN) and N-[N-(3,5-difluorophenacetyl)-l-alanyl]-s-phenylglycine t-butyl ester (DAPT), a specific inhibitor of Notch1 signalling) were administered via intraperitoneal injection to change oestrogen receptor β and Notch1 activities. Immunohistochemistry, western blot analysis, enzyme-linked immunosorbent assay (Elisa) assessment and echocardiography were used in this study to analyse cardiac oxidative stress, apoptosis, infraction volume, fibrosis and cardiac function.ResultsDPN-mediated oestrogen receptor β activation effectively protected cardiomyocytes from MI-induced oxidative damage and apoptosis. Furthermore, oestrogen receptor β activation reduced the infarct size and lowered the levels of myocardial enzymes in the serum, thereby leading to greater overall cardiac function improvement. Ischaemic injury-induced myocardial fibrosis was attenuated by oestrogen receptor β activation. Nevertheless, all of these cardioprotective effects of oestrogen receptor β activation were almost abrogated by DAPT administration, i.e. DAPT attenuated the anti-oxidative and anti-apoptotic effects and the decrease in infarct and fibrotic areas and reversed cardiac functional recovery. The levels of phospho-phosphatidylinositol-3-kinase (PI3K) and phospho-protein kinase B (Akt) were increased after DPN administration, and this change was reversed after DAPT was administered.ConclusionsAll of these new findings indicate that oestrogen receptor β activation is effective in ameliorating MI-induced cardiac dysfunction by enhancing Notch1 signalling and that PI3K/Akt signalling is the downstream mediator.
| S-EPMC7223456 | biostudies-literature
Project description:BackgroundGremlin-1 (GREM1), one of the bone morphogenetic protein antagonists, is involved in organogenesis, tissue differentiation and kidney development. However, the role of GREM1 in cancer progression and its underlying mechanisms remain poorly understood.MethodsThe role of GREM1 in breast cancer progression was assessed by measuring cell viability, colony formation, 3D tumour spheroid formation/invasion and xenograft tumour formation. Chromatin immunoprecipitation, a luciferase reporter assay and flow cytometry were performed to investigate the molecular events in which GREM1 is involved.ResultsGREM1 expression was elevated in breast cancer cells and tissues obtained from breast cancer patients. Its overexpression was associated with poor prognosis in breast cancer patients, especially those with oestrogen receptor (ER)-negative tumours. GREM1 knockdown inhibited the proliferation of breast cancer cells and xenograft mammary tumour growth, while its overexpression enhanced their viability, growth and invasiveness. Oestrogen-related receptor α (ERRα), an orphan nuclear hormone receptor, directly interacted with the GREM1 promoter and increased the expression of GREM1. GREM1 also enhanced the promoter activity of ESRRA encoding ERRα, comprising a positive feedback loop. Notably, GREM1 bound to and activated EGFR, a well-known upstream regulator of ERRα.ConclusionsOur study suggests that the GREM1-ERRα axis can serve as a potential therapeutic target in the management of cancer, especially ER-negative tumour.
| S-EPMC7493948 | biostudies-literature
Project description:BACKGROUND AND PURPOSE: Notoginsenoside R1 (NG-R1), a novel phytoestrogen isolated from Panax notoginseng, is believed to have anti-inflammatory, anti-oxidative and anti-apoptotic properties. However, its cardioprotective properties and underlying mechanisms are largely unknown. Here we have assessed the contribution of the anti-inflammatory effects of NG-R1 to the amelioration of septic cardiac dysfunction and inflammation in mice. EXPERIMENTAL APPROACH: We assessed cardiac function in mice by echocardiography. We studied the protein or mRNA levels of some inflammatory factors, apoptotic factors and oestrogen receptors (ERs) in heart tissues upon stimulation with bacterial LPS, NG-R1 or some pharmacological inhibitors. KEY RESULTS: Six hours after LPS administration (10 mg·kg(-1) , i.p.) cardiac function was decreased, an effect attenuated by NG-R1 pretreatment (25 mg·kg(-1) ·d(-1) , i.p.). NG-R1 also improved the imbalance between iNOS and eNOS, prevented activation of NF-?B and the subsequent myocardial inflammatory and apoptotic responses in endotoxemic mice. The effects of NG-R1 were closely associated with activation of the oestrogen receptor ER? and of PI3K/PKB (Akt) signalling, as characterized by NG-R1-induced preservation in ER?, phospho-Akt, phospho-GSK3? and I-?B?, and of cardiac function that was partially blocked by selective inhibitors of ER? or PI3K. However, NG-R1 had no effect on LPS-activated TLR-4. CONCLUSIONS AND IMPLICATIONS: NG-R1 is a promising compound for protecting the heart from septic shock, possibly via the activation of ER? and PI3K/Akt signalling. This mechanism produces blockade of NF-?B activation and attenuation of the pro-inflammatory state and apoptotic stress in the myocardium.
| S-EPMC3605881 | biostudies-other