Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA150235 | ENA |
REPOSITORIES: ENA
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Project description:Advanced ovarian cancer is the most lethal gynecologic malignancy in the United States. Currently patients are treated by surgical cytoreductive surgery with the aim of reducing tumor burden to microscopic disease followed by adjuvant combined treatment with a platinum and taxane containing chemotherapy, which affords 80% of patients an initial complete response. However, Abdominal and pelvic recurrence rates are high and response to further chemotherapy is limited. Attempts at introducing biologic therapeutic agents to improve outcome in this disease are ongoing, while prognostic or predictive biomarkers that can stratify patients for treatment are still lacking. Using a 60-mer 22K oligonucleotide-based array comparative genome hybridization (CGH) platform combined with DNA isolated from microdissected tumor tissue samples, Birrer et. al. reported that the amplification of 5q31-35.3 in ovarian cancer cells is a negative prognostic indicator for patients with advanced stage high-grade serous ovarian cancer (HGSC). Further studies showed that fibroblast growth factor 1 (FGF1) located in the amplicon, may be one of the driving genes for ovarian cancer progression (Birrer et. al., 2007). Besides FGF1, located on the same amplicon is one of its receptors fibroblast growth factor receptor 4 (FGFR4), suggesting that it may also be amplified and may be another driving gene involved in ovarian cancer pathogenesis.In this study, we used microarrays to explore and compare gene expression profiles between FGFR4 knock down ovarian cancer cell lines and their corresponding parental cell lines. Two high grade serous ovarian cancer cell lines: SKOV3 and OVCA432 were selected for this study. For each of the cell lines, two different siRNA sequences which both target human FGFR4 were used. While a non-target scramble siRNA sequence was used as control. Ovarian cancer cells were transfected with siRNA using lipofectamine (Invitrogen). RNA extraction was performed 72 hours post-transfection, followed by hybridization on Affymetrix microarrays.
2013-12-03 | E-GEOD-34828 | biostudies-arrayexpress
Project description:Advanced ovarian cancer is the most lethal gynecologic malignancy in the United States. Currently patients are treated by surgical cytoreductive surgery with the aim of reducing tumor burden to microscopic disease followed by adjuvant combined treatment with a platinum and taxane containing chemotherapy, which affords 80% of patients an initial complete response. However, Abdominal and pelvic recurrence rates are high and response to further chemotherapy is limited. Attempts at introducing biologic therapeutic agents to improve outcome in this disease are ongoing, while prognostic or predictive biomarkers that can stratify patients for treatment are still lacking. Using a 60-mer 22K oligonucleotide-based array comparative genome hybridization (CGH) platform combined with DNA isolated from microdissected tumor tissue samples, Birrer et. al. reported that the amplification of 5q31-35.3 in ovarian cancer cells is a negative prognostic indicator for patients with advanced stage high-grade serous ovarian cancer (HGSC). Further studies showed that fibroblast growth factor 1 (FGF1) located in the amplicon, may be one of the driving genes for ovarian cancer progression (Birrer et. al., 2007). Besides FGF1, located on the same amplicon is one of its receptors fibroblast growth factor receptor 4 (FGFR4), suggesting that it may also be amplified and may be another driving gene involved in ovarian cancer pathogenesis.In this study, we used microarrays to explore and compare gene expression profiles between FGFR4 knock down ovarian cancer cell lines and their corresponding parental cell lines.
2013-12-03 | GSE34828 | GEO
Project description:Breast cancer is the most common cancer among women. Among them, human epidermal growth factor receptor-positive (HER2+) breast cancer is more malignant. Fortunately, many anti-HER2 drugs are currently used in clinical treatments to increase patient survival. However, some HER2+ patients (~15%) still develop drug resistance after receiving trastuzumab treatment, leading to treatment failure. Using CCLE and METABRIC database analyses, we found that fibroblast growth factor receptor 4 (FGFR4) mRNA was highly detected in tumors from HER2+ breast cancer patients (P<0.001) and was associated with poorer survival in breast cancer patients. Through retrospective immunohistochemical staining analysis, we detected higher expression of FGFR4 protein in breast cancer tissues collected from patients who were resistant to trastuzumab therapy compared with breast cancer patients who responded to treatment. An FGFR4 inhibitor (FGF401) effectively inhibits tumor growth in trastuzumab-insensitive patient-derived xenograft (PDX) tumor-bearing mice. For molecular mechanism studies, we demonstrated that HER2/FGFR4 protein complexes were detected on the cell membrane of the tumor tissues in these trastuzumab-insensitive PDX tumor tissues. After trastuzumab treatment in these drug-resistant breast cancer cells, FGFR4 translocates and enters the nucleus. However, trastuzumab-induced nuclear translocation of FGFR4/HER2-intracellular domain protein complex in trastuzumab-resistant cancer cells is blocked by FGF401 treatment. We believe that FGFR4 overexpression and complex formation with HER2 can serve as molecular markers to assist clinicians in identifying trastuzumab-resistant tumors. Our results suggest that FGF401 combined with trastuzumab as adjuvant therapy for patients with trastuzumab-resistant breast cancer may be a potential new treatment strategy.
2024-11-08 | GSE262860 | GEO
Project description:Knock-down of ovarian cancer amplification target ADRM1 leads to down regulation of GIPC1 and up-regulation of RECK. Among 20q13-amplified genes in ovarian cancer, ADRM1 overexpression was the most highly correlated with amplification, and was significantly upregulated with respect to stage, recurrence and metastasis. In addition, overexpression of ADRM1 correlated significantly with shorter time to recurrence and overall survival. Herein, array-CGH and microarray expression of ovarian cancer cell lines, provides evidence consistent with the primary tumor data that ADRM1 is a 20q13 amplification target. Knock-down of ADRM1 in amplified ovarian cell line OAW42 results in down-regulation of growth factor GIPC1 and up-regulation of tumor-suppressor RECK RNA and protein. In our dataset of 141 ovarian primary tumors, ADRM1 overexpression significantly correlates with GIPC1 overexpression. In addition, there is a significant anticorrelation between ADRM1 overexpression and RECK expression. Further research is necessary to determine whether targeting knock-down of ADRM1 in 20q13-amplified ovarian cancers results in growth inhibition and tumor suppression via downstream targets GIPC1 and RECK.
2011-01-14 | GSE26634 | GEO
Project description:Knock-down of ovarian cancer amplification target ADRM1 leads to down regulation of GIPC1 and up-regulation of RECK. Among 20q13-amplified genes in ovarian cancer, ADRM1 overexpression was the most highly correlated with amplification, and was significantly upregulated with respect to stage, recurrence and metastasis. In addition, overexpression of ADRM1 correlated significantly with shorter time to recurrence and overall survival. Herein, array-CGH and microarray expression of ovarian cancer cell lines, provides evidence consistent with the primary tumor data that ADRM1 is a 20q13 amplification target. Knock-down of ADRM1 in amplified ovarian cell line OAW42 results in down-regulation of growth factor GIPC1 and up-regulation of tumor-suppressor RECK RNA and protein. In our dataset of 141 ovarian primary tumors, ADRM1 overexpression significantly correlates with GIPC1 overexpression. In addition, there is a significant anticorrelation between ADRM1 overexpression and RECK expression. Further research is necessary to determine whether targeting knock-down of ADRM1 in 20q13-amplified ovarian cancers results in growth inhibition and tumor suppression via downstream targets GIPC1 and RECK. ADRM1 siRNA treated OAW42 compared directly to untreated or nonspecific RNA treated OAW42
2011-01-14 | E-GEOD-26634 | biostudies-arrayexpress
Project description:Mechanisms driving tumor progression from less aggressive subtypes to more aggressive states represent key targets for breast cancer therapy. We identified a subset of Luminal A primary breast tumors to give rise to HER2-enriched (HER2E) subtype metastases, but remain clinically HER2 negative (cHER2-). By testing the unique genetic and transcriptomic features of these cases, we developed the hypothesis that fibroblast growth factor receptor 4 (FGFR4) drives this subtype switching. To evaluate this, we developed two FGFR4 genomic signatures using a PDX model treated with a FGFR4 inhibitor (BLU9931), which inhibited PDX growth in vivo. Examining patient outcomes in the METABRIC breast cancer cohort showed that the FGFR4-induced and FGFR4-repressed signatures each predicted overall survival (OS) (HR=6.30, P<0.0001; HR=0.33; P<0.0001, respectively). Multivariate analysis showed that the FGFR4-induced signature was also an independent prognostic factor beyond subtype and stage for OS (HR=2.34, P=0.014). Supervised analysis of 77 primary tumors with paired metastasis revealed that the FGFR4-induced signature was significantly higher in luminal/ER+ tumor metastases compared with their primaries. Finally, multivariate analysis demonstrated that the FGFR4-induced signature also predicted site-specific metastasis for lung, liver and brain, but not for bone or lymph nodes. These data identify a link between FGFR4-regulated genes and metastasis, suggesting a treatment options for FGFR4-positive patients, whose high expression is non-genetically determined.
2020-07-30 | GSE145326 | GEO
Project description:Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with increased risk in patients with metabolic syndrome. There are no FDA approved treatments, but farnesoid X receptor (FXR) agonists have shown promising results in clinical studies for NAFLD management. In addition to FXR, fibroblast growth factor receptor FGFR4 is a key mediator of hepatic bile acid synthesis. Using N-acetylgalactosamine-conjugated siRNA, we knocked down FGFR4 specifically in the liver of mice on chow or high-fat diet (HFD) and in mouse primary hepatocytes to determine the role of FGFR4 in metabolic processes and hepatic steatosis. Liver-specific FGFR4 silencing increased bile acid production and lowered serum cholesterol. Additionally, we found that HFD-induced liver steatosis and insulin resistance improved following FGFR4 knockdown. These improvements were associated with activation of the FXR-FGF15 axis in intestinal cells, but not in hepatocytes. We conclude that targeting FGFR4 in the liver to activate the intestinal FXR-FGF15 axis may be a promising strategy for the treatment of NAFLD and metabolic dysfunction.
2023-01-11 | GSE222499 | GEO
Project description:Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with increased risk in patients with metabolic syndrome. There are no FDA approved treatments, but farnesoid X receptor (FXR) agonists have shown promising results in clinical studies for NAFLD management. In addition to FXR, fibroblast growth factor receptor FGFR4 is a key mediator of hepatic bile acid synthesis. Using N-acetylgalactosamine-conjugated siRNA, we knocked down FGFR4 specifically in the liver of mice on chow or high-fat diet (HFD) and in mouse primary hepatocytes to determine the role of FGFR4 in metabolic processes and hepatic steatosis. Liver-specific FGFR4 silencing increased bile acid production and lowered serum cholesterol. Additionally, we found that HFD-induced liver steatosis and insulin resistance improved following FGFR4 knockdown. These improvements were associated with activation of the FXR-FGF15 axis in intestinal cells, but not in hepatocytes. We conclude that targeting FGFR4 in the liver to activate the intestinal FXR-FGF15 axis may be a promising strategy for the treatment of NAFLD and metabolic dysfunction.
2023-01-05 | GSE222171 | GEO
Project description:Mechanisms driving tumor progression from less aggressive subtypes to more aggressive states represent key targets for breast cancer therapy. We identified a subset of Luminal A primary breast tumors to give rise to HER2-enriched (HER2E) subtype metastases, but remain clinically HER2 negative (cHER2-). By testing the unique genetic and transcriptomic features of these cases, we developed the hypothesis that fibroblast growth factor receptor 4 (FGFR4) likely participates in this subtype switching. To evaluate this, we developed two FGFR4 genomic signatures using a PDX model treated with a FGFR4 inhibitor (BLU9931), which inhibited PDX growth in vivo. Bulk tumor gene expression analysis, and single cell RNAseq demonstrated that the inhibition of FGFR4 signaling caused molecular switching. Examining patient outcomes in the METABRIC breast cancer cohort showed that the FGFR4-induced and FGFR4-repressed signatures each predicted overall survival (OS) (HR=6.30, P<0.0001; HR=0.33; P<0.0001, respectively). Multivariate analysis showed that the FGFR4-induced signature was also an independent prognostic factor beyond subtype and stage for OS (HR=2.34, P=0.014). Supervised analysis of 77 primary tumors with paired metastasis revealed that the FGFR4-induced signature was significantly higher in luminal/ER+ tumor metastases compared with their primaries. Finally, multivariate analysis demonstrated that the FGFR4-induced signature also predicted site-specific metastasis for lung, liver and brain, but not for bone or lymph nodes. These data identify a link between FGFR4-regulated genes and metastasis, suggesting treatment options for FGFR4-positive patients, whose high expression is not caused by mutation or amplification.
2020-08-31 | GSE147322 | GEO
Project description:To understand the transcriptomic effect of FGF18 treatment on Chondrocytes cells from wt rat and on Chondrocytes obtained from a clone ko for the FGF receptors FGFR3 and FGFR4, we performed Quant-seq experiments. Both cell lines were treated with Fibroblast growth factor 18 (FGF18), while untreated cells were used as control.
2020-07-13 | GSE120516 | GEO