The effects of CEP-37440, an inhibitor of focal adhesion kinase, in vitro and in vivo on inflammatory breast cancer cells.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE73285 | GEO | 2015/12/14
SECONDARY ACCESSION(S): PRJNA296533
REPOSITORIES: GEO
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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. 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.
2015-12-14 | E-GEOD-73285 | biostudies-arrayexpress
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
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.
2012-09-20 | GSE40464 | GEO
Project description:Inflammatory breast cancer (IBC) is a rare type of breast cancer but accounts for up to 10% of breast cancer-related deaths. Plasticity between epithelial and mesenchymal feature is reported to be crucial in metastasis of IBC. Using Matigel culture, we induced epithelial to mesenchymal transition (EMT) in epithelial-like SUM149 IBC cells and identified overexpressed genes in this EMT process.
2018-04-01 | GSE109396 | GEO
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
Project description:Inflammatory Breast Cancer (IBC) is the most aggressive form of breast carcinoma characterized by the rapid onset of inflammatory signs. The molecular fingerprint for this rare, severe and unique clinical entity is still not elucidated. The goal of the present work was to detect both gene expression levels and alternate RNA splice variants specific to IBC. Experimental Design: In order to identify differentially expressed genes and splicing events, we performed splice-sensitive array profiling using Affymetrix Exon Array and quantitative RT-PCR analyses in a large series of 177 IBC compared to 183 non-IBC. We also assessed the prognostic value of the identified candidate genes and splice variants. Results: A 5-splice signature (HSPA8, RPL10, RPL4, DIDO1 and EVL) was able to distinguish IBC from non-IBC tumors (p<10-7). This splice signature was associated with poor metastasis-free survival (MFS) in hormone receptor-negative non-IBC (p=0.02), whereas it had no prognostic value in IBC patients. A PAM analysis of deregulated genes in IBC compared to non-IBC identified a 10-gene signature highly predictive of IBC phenotype and conferring a poor prognosis in non-IBC. The most up-regulated genes in IBC were 3 hemoglobin genes able to highly discriminate IBC from non IBC (p<10-4). In epithelial breast tumor cells, Hb protein expression was confirmed by immunohistochemistry. Conclusions: IBC has a specific spliced transcript profile that deserves further functional studies. Above all, IBC is characterized by hemoglobin genes overexpression, a fact that may lead to increased tumor progression. If confirmed, hemoglobins may serve as therapeutic targets.
2021-01-04 | GSE111477 | GEO
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
Project description:Inflammatory breast cancer (IBC) is a difficult-to-treat disease with poor clinical outcomes due to high risk of metastasis and resistance to treatment. We previously described a CD44+CD24-pSTAT3+ cancer cell subpopulation with stem cell-like features in breast cancer that is dependent on JAK/STAT3 signaling. Here we report that CD44+CD24- cells are the most frequent cell-type in IBC and are commonly pSTAT3+. Combination of JAK/STAT3 inhibition with paclitaxel decreased IBC xenograft growth more than either agent alone. We developed and characterized IBC cell lines resistant to paclitaxel and doxorubicin to mimic therapeutic resistance in patients. Multi-omic profiling of parental and resistant cells revealed genes associated with lineage identity and inflammation were enriched in chemotherapy resistant derivatives. Integrated pSTAT3 ChIP-seq and RNA-seq analyses showed pSTAT3 regulates genes related to inflammation and epithelial to mesenchymal transition (EMT) in resistant cells, as well as PDE4A, a cAMP-specific phosphodiesterase. Metabolomic characterization identified elevated cAMP signaling and CREB as a candidate therapeutic target in IBC. We also investigated cellular dynamics and heterogeneity at the single cell level during chemotherapy and acquired resistance by CyTOF and single cell RNA-seq. We identified mechanisms of resistance including a shift from luminal to basal/mesenchymal cell states through selection for rare pre-existing subpopulations or an acquired change. Lastly, we showed that combination treatment with paclitaxel and JAK/STAT3 inhibition prevented the emergence of this more mesenchymal chemo-resistant subpopulation. Our results provide mechanistic rational for combination of chemotherapy with inhibition of JAK/STAT3 signaling as a new more effective therapeutic strategy in IBC.
2022-11-04 | MSV000090647 | MassIVE
Project description:ZBP1/IMP1 is an mRNA binding protein that post-transcriptionally regulates the expression of a handful mRNAs, implicated in maintaining cell polarity and adhesion. We have previously shown that ZBP1 was able to inhibit proliferation and invasiveness of breast carcinoma cells in vitro. In the current study, we utilized orthotopic breast fat pad xenografts to further investigate the ZBP1-mediated functions in breast tumorigenesis and metastasis in vivo. We used microarrays to identify important gene for breast tumor growth and metastasis in response to ZBP1 expression
2014-10-24 | GSE62638 | GEO
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