High-resolution comparative genomic hybridization of inflammatory breast cancer and identification of candidate genes
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE23720 | GEO | 2011/03/01
SECONDARY ACCESSION(S): PRJNA130683
REPOSITORIES: GEO
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Project description:Inflammatory breast cancer (IBC) is an aggressive form of BC poorly defined at the molecular level. We compared the molecular portraits of 63 IBC and 134 non-IBC (nIBC) clinical samples. Genomic imbalances of 49 IBCs and 124 nIBCs were determined using high-resolution array-comparative genomic hybridization, and mRNA expression profiles of 197 samples using whole-genome microarrays. Genomic profiles of IBCs were as heterogeneous as those of nIBCs, and globally relatively close. However, IBCs showed more frequent “complex” patterns and a higher percentage of genes with CNAs per sample. The number of altered regions was similar in both types, although some regions were altered more frequently and/or with higher amplitude in IBCs. Many genes were similarly altered in both types; however, more genes displayed recurrent amplifications in IBCs. Pre-treatment tumor tissues were collected from 197 patients with invasive adenocarcinomas. Patients underwent surgical biopsies or initial surgery at the Institut Paoli-Calmettes (IPC, Marseille, France) between 1987 and 2007. Each patient gave written informed consent and the study was approved by the IPC “Comité d’Orientation Stratégique”. Tumor samples were macrodissected and frozen in liquid nitrogen within 30 minutes of removal. Before RNA extraction, tumor sections were reviewed by two pathologists and contained more than 60% of tumor cells. Gene expression data of the 197 BCs were quantified using whole-genome DNA microarrays (HG-U133 Plus 2.0, Affymetrix).
2011-03-01 | E-GEOD-23720 | biostudies-arrayexpress
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
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:Tumor epithelium and surrounding stromal cells were isolated using laser capture microdissection of human breast cancer to examine differences in gene expression based on tissue types from inflammatory and non-inflammatory breast cancer Experiment Overall Design: We applied LCM to obtain samples enriched in tumor epithelium and stroma from 15 IBC and 35 non-IBC cases to study the relative contribution of each component to the IBC phenotype and to patient survival.
2008-06-14 | E-GEOD-5847 | 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 and aggressive type of breast cancer (BC) whose molecular basis is poorly understood. We performed a comprehensive molecular analysis of 24 fresh frozen IBC biopsies naïve of treatment, using a high-resolution microarray platform The most common genes covered by copy number alterations included gains of MYC and MDM4, and losses affecting TP53 and RB1. MYC and MDM4 genes have been related to IBC aggressiveness, and MDM4 might also represent a new therapeutic target in IBC. Thirteen IBC cases presented copy-neutral of heterozygosity (cnLOH) or losses covering CHL1, which gives additional evidence of its role as a tumor suppressor. Functional enrichment analysis with the most common alterations revealed genes associated with inflammatory regulation and immune response. Particularly, IL6R and IL7 could represent therapeutic targets for IBC treatment. Chromothripsis patterns were identified in nine cases and chromosomal instability in 50% of cases. High homologous recombination (HR) deficiency scores were observed in triple-negative IBC and those with metastasis. High telomeric allelic imbalance (TAI) score was detected in patients having worse overall survival (OS). TAI score could also be useful to predict deficiency in homologous recombination (HR) genes and to identify patients for platinum or PARP inhibitor therapy. Our study describes the most common genomic alterations in IBC and their association with clinical findings, providing a framework for improved diagnosis and therapeutic opportunities for this aggressive tumor type.
2020-01-24 | GSE144015 | 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+ breast cancer cell subpopulation with stem cell-like features that is dependent on JAK2/STAT3 signaling. Here we report that CD44+CD24- cells are the most frequent cell-type in IBC and are commonly pSTAT3+. Combination of JAK2/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 JAK2/STAT3 inhibition prevented the emergence of this more mesenchymal chemo-resistant subpopulation. Our results provide mechanistic rational for combination of chemotherapy with inhibition of JAK2/STAT3 signaling as a new more effective therapeutic strategy in IBC.
2022-11-02 | GSE163360 | 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+ breast cancer cell subpopulation with stem cell-like features that is dependent on JAK2/STAT3 signaling. Here we report that CD44+CD24- cells are the most frequent cell-type in IBC and are commonly pSTAT3+. Combination of JAK2/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 JAK2/STAT3 inhibition prevented the emergence of this more mesenchymal chemo-resistant subpopulation. Our results provide mechanistic rational for combination of chemotherapy with inhibition of JAK2/STAT3 signaling as a new more effective therapeutic strategy in IBC.
2022-11-02 | GSE163836 | 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+ breast cancer cell subpopulation with stem cell-like features that is dependent on JAK2/STAT3 signaling. Here we report that CD44+CD24- cells are the most frequent cell-type in IBC and are commonly pSTAT3+. Combination of JAK2/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 JAK2/STAT3 inhibition prevented the emergence of this more mesenchymal chemo-resistant subpopulation. Our results provide mechanistic rational for combination of chemotherapy with inhibition of JAK2/STAT3 signaling as a new more effective therapeutic strategy in IBC.
2022-11-02 | GSE213870 | 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