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The effects of CEP-37440, an inhibitor of focal adhesion kinase, in vitro and in vivo on inflammatory breast cancer cells.

ABSTRACT: CEP-37440 at low concentration (1,000 nM) decreased the proliferation of the human inflammatory breast cancer (IBC) cell line FC-IBC02, while not affecting the proliferation of normal breast epithelial cells. CEP-37440 decreased the cell proliferation of FC-IBC02 by blocking the auto-phosphorylation kinase activity of FAK (Tyr 397). This cell line did not expressed ALK. In vivo, CEP-37440 significantly decreased FC-IBC02 breast tumor xenografts growth with maximum of 40% tumor growth inhibition. None of the FC-IBC02 breast xenografts mice treated with CEP-37440 developed brain metastasis in contrast to the control group in which 20% of the mice developed brain metastasis. Expression array analyses in FC-IBC02 cells showed that CEP-37440 affects the expression of genes related to apoptosis specifically related to the interferon signaling pathway. Cell proliferation assays were performed in the presence of several concentrations of CEP-37440 using IBC and triple negative breast cancer (TNBC) non-IBC cell lines. We studied the expression of total FAK1, phospho-FAK1 (Tyr 397), total ALK and phospho-ALK (Tyr 1604) in these cells by ELISA. FC-IBC02 cells were treated with 1,000 nM CEP-37440 during 48 h, and expression arrays were performed in order to define pathways dysregulated by CEP-37440.

ORGANISM(S): Homo sapiens

SUBMITTER: Sandra Fernandez

PROVIDER: E-GEOD-73285 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The effects of CEP-37440, an inhibitor of focal adhesion kinase, in vitro and in vivo on inflammatory breast cancer cells.

Project description:CEP-37440 at low concentration (1,000 nM) decreased the proliferation of the human inflammatory breast cancer (IBC) cell line FC-IBC02, while not affecting the proliferation of normal breast epithelial cells. CEP-37440 decreased the cell proliferation of FC-IBC02 by blocking the auto-phosphorylation kinase activity of FAK (Tyr 397). This cell line did not expressed ALK. In vivo, CEP-37440 significantly decreased FC-IBC02 breast tumor xenografts growth with maximum of 40% tumor growth inhibition. None of the FC-IBC02 breast xenografts mice treated with CEP-37440 developed brain metastasis in contrast to the control group in which 20% of the mice developed brain metastasis. Expression array analyses in FC-IBC02 cells showed that CEP-37440 affects the expression of genes related to apoptosis specifically related to the interferon signaling pathway.

2015-12-14 | GSE73285 | GEO

Expression of SUDHL-1 cell line treated by ALK inhibitors

Project description:In this study we compared the effects of ALK inhibitor on the gene expression, activation of cell signaling pathways, and functional properties of cells derived from a patient with Anaplastic Large Cell Lymphoma. we used microarrays to map the genome-wide gene expression patterns in ALK+TCL cells in response to ALK inhibition. The ALK+TCL Sudhl-1 cell line was treated in triplicates with the ALK inhibitor, CEP-14083, or the compound's solvent for 6 h. The isolated RNA was reverse-transcribed, biotin-labeled, and hybridized to the U133 Plus 2.0 array chips (Affymetrix). Microarray data were normalized using the MAS5 algorithm and analyzed using Partek GS (Partek).

2013-10-31 | E-GEOD-50803 | biostudies-arrayexpress

FC-IBC-02: A New in vitro-in vivo Model of Triple Negative Inflammatory Breast Cancer

Project description:Inflammatory breast cancer (IBC) is the most aggressive type of advanced breast cancer and is associated with a poor prognosis. We have developed a new model of IBC derivated from the pleural effusion of a 49-year-old woman with metastatic secondary IBC. FC-IBC02 tumor cells were isolated from the pleural effusion and cultured under non-adherent conditions, resulting in the formation of spheroids or mammospheres. FC-IBC02 are triple negative (estrogen receptor negative, progesterone receptor negative and ErbB2 negative) and strongly positive for E-cadherin, beta-catenin and vimentin. FC-IBC02 cells developed breast tumors when they were injected into the mammary fat pad of SCID mice and characteristic tumor emboli were detected. Breast tumor xenografts were poorly differentiated triple negative carcinomas and all injected mice developed metastasis in the lungs and lymph nodes. These IBC tumor cells showed genomic alterations in all chromosomes, with the gains/amplifications more common than the deletions/losses. Duplicated regions were on 1q, 2p, 3q, 8q and 18p and chromosomes 7 and 9. The 8q chromosome arm where the MYC oncogene resides was amplified up to seven fold. Chromothripsis (local chromosome shattering) was observed on chromosome 11q and losses were found on 8p, 11q, 16q and 17p (location of TP53). FC-IBC-02 cells expressed the stem cell marker CD44, EpCAM and strongly expressed EGFR and ALK. In summary, this novel preclinical model demonstrated that IBC is a disease enriched for highly tumorigenic cells which harbor a stem cell phenotype. This IBC model is ideal for the study of the metastatic process and to evaluate targeting therapeutic modalities. Total RNA were isolated from IBC-02, IBC-02 in mammosphere growth, IBC3, SUM149, SUM190, MDA-MB231, and MDA-MB468 cell lines. Affymetrix Human U133 Plus 2.0 arrays were used for whole-genome gene expression assays. Duplicate samples were analyzed for each cell line.

2012-09-20 | E-GEOD-40464 | biostudies-arrayexpress

FC-IBC-02: A New in vitro-in vivo Model of Triple Negative Inflammatory Breast Cancer

2012-09-20 | GSE40464 | GEO

N-glycoproteomic profiling reveals new therapeutic targets against coronavirus infestation which may be involved in Cepharanthine’s intervention

Project description:N-glycosylation is an important post-translational modification involved in protein folding, signal transduction, extracellular matrix (ECM) organization and immune response. Recent evidence shows that SARS-CoV-2 Spike protein is highly glycosylated and it may be potential target in viral pathology and drug/vaccine design. Therefore, the N-glycoproteomic profiling of coronavirus and its infected cells are of great importance in therapeutic targets screening for drug discovery. Here, we carried out 4D label-free LC-MS/MS-based N-glycoproteomics using a well-established SARS-CoV-2 cellular model, pangolin GX_P2V virus-infected Vero E6 cells, to study the mechanism of coronavirus infestation and potential drug targets. Meanwhile, we investigated the effect of Cepharanthine (CEP) on viral-induced aberrant N-glycoprotein changes in affected cells and on the viral proteins. The results showed that coronavirus GX_P2V could cause aberrant glycosylation of cell proteins at multiple levels, including extracellular matrix (ECM) and related signal transduction, whereas CEP can maintain 12 out of 69 GX_P2V-induced aberrant glycoproteins at normal glycosylation state. Functional enrichment and PPI analyses revealed that LAMB1 and FN1 were the pivotal proteins in regulating the aberrant glycosylation caused by coronavirus in presence of CEP, indicating that CEP might achieve its therapeutic intervention via these potential targets. Besides, CEP can regulate the glycosylation of viral proteins S, M and N. Nevertheless, there were still 57 out of 69 glycoproteins which cannot be significantly affected by CEP, indicating the combination of CEP with other drugs against the rest of targets should be considered.

2022-08-12 | PXD021297 | Pride

Kininogen–Nitric Oxide Signaling at Nearby Non-excited Acupoints After Long-term Stimulation

Project description:Acupuncture treatment is based on acupoint stimulation; however, the biological basis is not understood. We stimulated one acupoint with catgut embedding (CEP) for 8 weeks and then used isobaric tags for relative and absolute quantitation to screen proteins with altered expression in adjacent acupoints of Sprague Dawley rats. The expression levels of 10 proteins, including kininogen (KNG), consistently changed >1.5-fold in all three acupoints in CEP versus sham CEP-treated rats. Eight-week, but not 3-day, CEP treatment enhanced KNG expression. The enhanced KNG expression among small vessels in the subcutaneous layer was revealed via immunofluorescence. Nitric oxide synthesis was enhanced similar to KNG. These findings uncover biological changes at acupoints and suggest the critical role of the KNG–nitric oxide signaling pathway in acupoint activation.

2022-02-16 | PXD024018 | Pride

Transcriptomic analysis of A3250 inflammatory breast cancer (IBC) cells, SUM149 IBC and MDA-MB-231 non-IBC cells

Project description:Purpose: Transcriptome profiling (RNA-seq) of a novel human Inflammatory Breast Cancer cell line A3250 in comparison to SUM149 and MDA-MB-231 Inflammatory Breast Cancer (IBC) is the most aggressive form of breast cancer with distinct clinical and histopathological features, but understanding of the unique aspects of IBC biology lags far behind that of other breast cancers. We describe a novel triple-negative IBC cell line, A3250, that recapitulates key features of human IBC in a mouse xenograft model.The purpose of this study was to compare differences in gene expression between A3250 IBC, MDA-MB-231 non-IBC and SUM149 IBC that does not present with typical clinical sympotms of IBC in a mouse model, with the goal of identifying unique molecular features for this unique type of breast cancer Results: RNA-Seq analysis identified expression profile characteristic for the novel A3250 IBC cell line, compared to SUM149 IBC and MDA-MB-231 non-IBC.

2021-10-01 | GSE180788 | GEO

Gene expression profile of breast cancer cell lines

Project description:Inflammatory Breast Cancer (IBC) is the most aggressive form of breast cancer, but understanding of the unique aspects of IBC biology lags far behind that of other breast cancers. One of the key barriers in advancing understanding of the molecular determinants of IBC has been the lack of adequate models for this disease that presents with distinct clinical and histopathological features. We describe here a novel human triple-negative IBC cell line, A3250, that recapitulates key features of human IBC in a mouse orthotopic model including skin erythema, diffuse tumor growth, high stroma to tumor ratio, dermal lymphatic invasion, and extensive lymph node and distant metastases. Tumor-associated macrophages were particularly enriched, and A3250 cells expressed very high levels of CCL2, a macrophage recruiting chemokine in the absence of detectable levels of its cognate receptor. CCL2 knockdown led to a striking reduction in macrophage densities, tumor cell proliferation, and metastasis in vivo. These results identify tumor-derived CCL2 as a key factor driving macrophage expansion and indirectly, the growth of A3250 IBC cells in vivo. Comparison of the A3250 chemokine expression profile with human IBC expression data sets revealed sharing of this profile across different IBC subtypes as well as enrichment for macrophage expression. Thus, this human IBC model provides a unique opportunity to uncover novel aspects of IBC biology, and to test novel therapies for this deadly disease.

2023-09-30 | GSE159987 | GEO

Genomic Analysis of Microdissected Inflammatory Breast Cancer

Project description:Inflammatory breast cancer (IBC) is a unique clinical entity characterized by rapid onset of erythema and swelling of the breast often without an obvious breast mass. Many studies have examined and compared gene expression between IBC and non-IBC (nIBC), repeatedly finding clusters associated with receptor subtype, but no consistent gene signature associated with IBC has been validated. Here we examined microdissected IBC tumor cells compared to microdissected nIBC tumor cells matched based on estrogen and HER-2/neu receptor status. Genomic profiling of 20 inflammatory breast cancer (IBC), 20 non-IBC and 5 normal was studied.

2013-03-29 | E-GEOD-45582 | biostudies-arrayexpress

Expression Analysis of Microdissected Inflammatory Breast Cancer

Project description:Inflammatory breast cancer (IBC) is a unique clinical entity characterized by rapid onset of erythema and swelling of the breast often without an obvious breast mass. Many studies have examined and compared gene expression between IBC and non-IBC (nIBC), repeatedly finding clusters associated with receptor subtype, but no consistent gene signature associated with IBC has been validated. Here we examined microdissected IBC tumor cells compared to microdissected nIBC tumor cells matched based on estrogen and HER-2/neu receptor status. Gene expression profiling of 20 inflammatory breast cancer (IBC), 20 non-IBC and 5 normal was studied.

2013-03-29 | E-GEOD-45581 | biostudies-arrayexpress

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