Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA205252 | ENA |
REPOSITORIES: ENA
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Project description:Human breast cancer SKBr-3 cells selected with trastuzumab for 6 month compared with parental SKBr-3 cells; Goal was to screen for microRNAs involved in development of trastuzumab resistance. Human breast cancer SKBr-3 cells were continuously cultured in the presence ofM-BM- 5M-BM-5g/ml trastuzumab for 6 months, and the resulting alive cells were regarded as trastuzumab-resistant. Total RNAs were prepared from these cells and cells cultured in parallel in control media, and were subjected to hybridization on the miRCURY LNA Array (Exiqon, version 11.0).
2013-05-25 | E-GEOD-47011 | biostudies-arrayexpress
Project description:Human breast cancer SKBr-3 cells selected with trastuzumab for 6 month compared with parental SKBr-3 cells; Goal was to screen for microRNAs involved in development of trastuzumab resistance.
2013-05-25 | GSE47011 | GEO
Project description:The intention was to detect genes that are determining trastuzumab efficiency in HER2-positive breast cancer cell lines with different resistance phenotypes. While BT474 should be sensitive to the drug treatment, HCC1954 is expected to be resistant due to a PI3K mutation. The cell line BTR50 has been derived from BT474 and was cultured to be resistant as well. Based on RNA-Seq data, we performed differential expression analyses on these breast cancer cell lines with and without trastuzumab treatment. In detail, five separate tests were performed, namely resistant cells vs. wild type, i.e. HCC1954 and BTR50 vs. BT474, respectively, and untreated vs. drug treated cells. The significant genes of the first two tests should contribute to resistance. The significant genes of the test BT474 vs. its drug treated version should contribute to the trastuzumab effect. To exclude false positives from the combined gene set (#64), we removed ten genes that were also significant in the test BTR50 vs. its drug treated version. This way we ended up with 54 genes that are very likely to determine trastuzumab efficiency in HER2-positive breast cancer cell lines. mRNA profiles of human breast cancer cell lines were generated by deep sequencing using Illumina HiSeq 2000. The cell lines BT474 and HCC1954 were analyzed with and without trastuzumab treatment. HCC1954 is known to be trastuzumab resistant. Additionally, the cell line BTR50 was generated as resistant version of BT474, and was analyzed with and without trastuzumab as well.
2015-04-21 | E-GEOD-55005 | biostudies-arrayexpress
Project description:Acquired resistance to trastuzumab, a rationally designed HER-2 targeting antibody, remains a major hurdle in management of HER-2 positive breast cancer (HER-2+ BC) patients. Potential resistance mechanisms are numerous, derived primarily from studies where HER-2 positive cell lines are chronically exposed to trastuzumab. Recent evidence suggests a role for epithelial-mesenchymal transition (EMT) in trastuzumab resistance, but a definitive link between the two has been difficult to establish because relevant model systems are lacking. When sub-populations of trastuzumab sensitive SKBR-3 cells were isolated using cloning rings, an (EMT) occurred spontaneously in several (3/8) clones. SKBR-3 EMT-clones featured increased spindle morphology, expressed N-glycosylated M-NM-21-integrin, and decreased HER-2, all characteristics shared by JIMT-1, a cell lines with intrinsic resistance to trastuzumab. SKBR-3 EMT-clones were characterized by gene expression profiling and mammosphere formation. The N-glycosylated isoform of M-NM-2-itnegrin was targeted with M-NM-2-integrin inhibiting antibody, AIIB2. Transcriptional profiling revealed that SKBR-3 EMT-clones underwent a shift from a luminal molecular subtype to a more aggressive mesenchymal/ basal phenotype. Isolating clones from SKBR-3 cells with enforced expression of a M-NM-2-integrin isoform lacking extensive N-glycosylation failed to increase the likelihood for spontaneous EMT in SKBR-3. However, specific inhibition of the heavily N-glycosylated variant of M-NM-21-integrin expressed by SKBR-3 EMT-clones restored epithelial morphology and impaired mammosphere formation. Furthermore, when SKBR-3 EMT-clones were treated with relevant doses of trastuzumab and lapatinib, they showed M-bM-^@M-^\spontaneousM-bM-^@M-^] resistance. In this study we describe a model of spontaneous EMT following clonal selection in HER-2+ cell line, SKBR-3. Using this model we establish the first direct link between EMT and resistance to HER-2 targeted therapies. We also identify the N-glycosylated isoform of M-NM-2-integrin as a potential biomarker and target in HER-2+ BC refractory to HER-2 targeted therapies. RNA was isolated from 10 breast cancer cell lines in triplicate. Pairwise gene expression differences were compared between each of the SKBR-3 cell lines (SKBR-3/ b1, SK-EV-C4, and SK-B1-C1). Features selected had at least a 2X difference in at least one comparison, with a one-way ANOVA corrected p-value of >0.05. In addition, expression profiles from SKBR-3/ EV and SK-B1-C1 cell were compared and a differential gene list was generated to include genes that differed by at least 1.5X, with a t-test p-value of >0.02 (unpaired, Bonferroni corrected). A total of 1940 entities met these criteria and the expression of these genes was investigated in all breast cancer cell lines.
2015-01-01 | E-GEOD-40152 | biostudies-arrayexpress
Project description:The intention was to detect genes that are determining trastuzumab efficiency in HER2-positive breast cancer cell lines with different resistance phenotypes. While BT474 should be sensitive to the drug treatment, HCC1954 is expected to be resistant due to a PI3K mutation. The cell line BTR50 has been derived from BT474 and was cultured to be resistant as well. Based on RNA-Seq data, we performed differential expression analyses on these breast cancer cell lines with and without trastuzumab treatment. In detail, five separate tests were performed, namely resistant cells vs. wild type, i.e. HCC1954 and BTR50 vs. BT474, respectively, and untreated vs. drug treated cells. The significant genes of the first two tests should contribute to resistance. The significant genes of the test BT474 vs. its drug treated version should contribute to the trastuzumab effect. To exclude false positives from the combined gene set (#64), we removed ten genes that were also significant in the test BTR50 vs. its drug treated version. This way we ended up with 54 genes that are very likely to determine trastuzumab efficiency in HER2-positive breast cancer cell lines.
2015-04-21 | GSE55005 | GEO
Project description:Acquired resistance to trastuzumab, a rationally designed HER-2 targeting antibody, remains a major hurdle in management of HER-2 positive breast cancer (HER-2+ BC) patients. Potential resistance mechanisms are numerous, derived primarily from studies where HER-2 positive cell lines are chronically exposed to trastuzumab. Recent evidence suggests a role for epithelial-mesenchymal transition (EMT) in trastuzumab resistance, but a definitive link between the two has been difficult to establish because relevant model systems are lacking. When sub-populations of trastuzumab sensitive SKBR-3 cells were isolated using cloning rings, an (EMT) occurred spontaneously in several (3/8) clones. SKBR-3 EMT-clones featured increased spindle morphology, expressed N-glycosylated β1-integrin, and decreased HER-2, all characteristics shared by JIMT-1, a cell lines with intrinsic resistance to trastuzumab. SKBR-3 EMT-clones were characterized by gene expression profiling and mammosphere formation. The N-glycosylated isoform of β-itnegrin was targeted with β-integrin inhibiting antibody, AIIB2. Transcriptional profiling revealed that SKBR-3 EMT-clones underwent a shift from a luminal molecular subtype to a more aggressive mesenchymal/ basal phenotype. Isolating clones from SKBR-3 cells with enforced expression of a β-integrin isoform lacking extensive N-glycosylation failed to increase the likelihood for spontaneous EMT in SKBR-3. However, specific inhibition of the heavily N-glycosylated variant of β1-integrin expressed by SKBR-3 EMT-clones restored epithelial morphology and impaired mammosphere formation. Furthermore, when SKBR-3 EMT-clones were treated with relevant doses of trastuzumab and lapatinib, they showed “spontaneous” resistance. In this study we describe a model of spontaneous EMT following clonal selection in HER-2+ cell line, SKBR-3. Using this model we establish the first direct link between EMT and resistance to HER-2 targeted therapies. We also identify the N-glycosylated isoform of β-integrin as a potential biomarker and target in HER-2+ BC refractory to HER-2 targeted therapies.
2015-01-01 | GSE40152 | 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:Human breast cancer cells: parental v.s lapatinib-resistant clone
| PRJNA225686 | ENA
Project description:We established an acquired trastuzumab-resistant model in vitro from a trastuzumab-sensitive, HER2-amplified breast-cancer cell line. A multi-omic strategy was implemented to obtain gene, proteome, and phosphoproteome signatures associated with acquired resistance to trastuzumab in HER2-positive breast cancer, followed by validation in human clinical samples.
2020-06-01 | PXD010574 | Pride
Project description:Background: Central nervous system (CNS) metastases represent a major problem in the treatment of HER2-positive breast cancer due to the disappointing efficacy of HER2-targeted therapies in the brain microenvironment. The antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) has shown efficacy in trastuzumab-resistant systemic breast cancer. Here, we tested the hypothesis that T-DM1 could overcome trastuzumab resistance in preclinical models of brain metastases. Methods: We treated mice bearing BT474 or MDA-MB-361 tumors in the CNS (N=9-11 per group), or cancer cells grown in organotypic brain slice cultures with trastuzumab or T-DM1 at equivalent or equipotent doses. Using intravital imaging, molecular techniques and histological analysis we determined tumor growth, mouse survival, cancer cell apoptosis and proliferation, tumor drug distribution, and HER2 signaling. All statistical tests were two-sided. Results: T-DM1 significantly delayed the growth of HER2-positive breast cancer brain metastases compared to trastuzumab. These findings were consistent between HER2-driven and PI3K-driven tumors. The activity of T-DM1 resulted in a striking survival benefit (median survival for BT474 tumors: 28d for trastuzumab vs 112d for T-DM1, HR=6.2, 95% CI=6.1 to 85.84; P<.001). No difference in drug distribution and HER2-signaling was revealed between the two groups. However, T-DM1 led to a significant increase in tumor cell apoptosis (One-way ANOVA for ApopTag, p<.001), which was associated with mitotic catastrophe. Conclusions: T-DM1 can overcome resistance to trastuzumab therapy in HER2-driven and PI3K-driven breast cancer brain lesions due to the cytotoxicity of the DM1 component. Clinical investigation of T-DM1 for patients with CNS metastases from HER2-positive breast cancer is warranted. Comparison of trastuzumab (n=4) and TDM-1 (n=4) treated BT-474 human breast carcinoma cells growing in murine brain
2015-11-09 | E-GEOD-69042 | biostudies-arrayexpress