The HER2 amplicon includes several genes required for the growth and survival of HER2 positive breast cancer cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Henrik Edgren
PROVIDER: E-GEOD-34236 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Thirteen HER2 positive breast cancer cell lines were screened with 22 commercially available compounds, mainly targeting proteins in the ErbB2 signaling pathway, and the molecular mechanisms related to treatment response were sought. To search for response predictors, genomic and transcriptomic profiling, PIK3CA mutations and PTEN status were associated to the drug responses and several genes involved in the response of the compounds were identified. Array-CGH experiments of HER2+ breast cancer cell lines grown under standard conditions. DNA from four HER2 positive breast cancer cell lines was isolated and hybridized on Agilent arrays.
2015-01-30 | E-GEOD-58886 | biostudies-arrayexpress
Project description:Array-CGH experiments of HER2+ breast cancer cell lines grown under standard conditions.
2013-06-01 | GSE34236 | GEO
Project description:About 20% of breast cancers are characterized by amplification and overexpression of the HER2 oncogene. Although significant progress has been achieved for treating such patients with HER2 inhibitor trastuzumab, more than half of the patients respond poorly or become resistant to the treatment. Since the HER2 amplicon at 17q12 contains multiple genes, we have systematically explored the role of the HER2 co-amplified genes in breast cancer cell growth and their relation to trastuzumab resistance. We integrated aCGH data of the HER2 amplicon from 71 HER2 positive breast tumors and 10 cell lines with systematic functional RNA interference analysis of 23 core amplicon genes with several phenotypic endpoints in a panel of trastuzumab responding and non-responding HER2 positive breast cancer cells. Silencing of HER2 caused a greater growth arrest and apoptosis in the responding compared to the non-responding cell lines, indicating that the resistant cells are inherently less dependent on the HER2 pathway. Several other genes in the amplicon also showed a more pronounced effect when silenced; indicating that expression of HER2 co-amplified genes may be needed to sustain the growth of breast cancer cells. Importantly, co-silencing of STARD3, GRB7, PSMD3 and PERLD1 together with HER2 led to an additive inhibition of cell viability as well as induced apoptosis. These studies indicate that breast cancer cells may become addicted to the amplification of several genes that reside in the HER2 amplicon. The simultaneous targeting of these genes may increase the efficacy of the anti-HER2 therapies and possibly also counteract trastuzumab resistance. The observed additive effects seem to culminate to both apoptosis and cell proliferation pathways indicating that these pathways may be interesting targets for combinatorial treatment of HER2+ breast cancers.
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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-01-30 | E-GEOD-58887 | biostudies-arrayexpress
Project description:A large number of breast cancers are characterized by amplification and overexpression of the chromosome segment surrounding the HER2 (ERBB2) oncogene. As the HER2 amplicon at 17q12 contains multiple genes, we have systematically explored the role of the HER2 co-amplified genes in breast cancer cell growth and their relation to trastuzumab resistance. We integrated array comparative genomic hybridization (aCGH) data of the HER2 amplicon from 71 HER2 positive breast tumors and 10 cell lines with systematic functional RNA interference analysis of 23 core amplicon genes with several phenotypic endpoints in a panel of trastuzumab responding and non-responding HER2 positive breast cancer cells. In this Data in Brief we give a detailed description of the experimental procedures and the data analysis methods used in the study (1).
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Project description:Using high-resolution, array-based comparative genomic hybridization (aCGH), we explored genomic alterations in 40 fresh-frozen ACC samples, the largest cohort to date, with the aims to: (1) identify recurrent CNAs in ACC; (2) identify novel candidate target genes; and (3) correlate recurrent CNAs with tumour grade and other clinical parameters to identify potential clinically useful biomarkers. High-resolution aCGH on fresh frozen tissue from 40 ACCs.
2012-12-31 | E-GEOD-34816 | biostudies-arrayexpress
Project description:Amplification of chromosome 17q23 is a frequent genomic event that occurs in ~ 11% of human breast cancers. The 17q23 amplification is enriched in HER2+ breast cancers, which is significantly correlated with poor clinical outcomes. Previous studies have identified the oncogenic phosphatase WIP1 gene in the amplicon, which functions as a master inhibitor in DNA damage response. While the possibility of any other protein-coding oncogenes in the WIP1-containing 17q23 amplicon was ruled out, our analysis of human breast cancer genomics uncovered an oncogenic microRNA gene, MIR21, in a majority of the WIP1-containing amplicons. Interestingly, DEAD-box helicase 5 (DDX5), co-amplified with WIP1 and MIR21 in the 17q23 amplicon, facilitates the essential processing of primary miR-21 transcripts. Accordingly, the 17q23 amplification results in aberrant expression of WIP1 and miR-21, which not only promotes breast tumorigenesis, but also leads to resistance to anti-HER2 therapies. Inhibiting WIP1 and miR-21 using small molecular inhibitor against WIP1 (GSK2830371) and anti-miR-21 oligonucleotides selectively inhibits the proliferation, survival and tumorigenic potential of HER2+ breast cancer cells harboring 17q23 amplification. However, the in vivo bioavailability of the two agents in their free form is poor. To overcome the resistance of trastuzumab-based therapies in vivo, we developed pH-sensitive nanoparticles for specific co-delivery of the two agents into breast tumors. The nanoparticles consist of four materials approved by the Food and Drug Administration (FDA) for medical use: Poly (d,l-lactide-co-glycolide) (PLGA), Pluronic F127 (PF127), chitosan, and 1,2-dipalmitoyl-sn-glycerol-3-phosphocholine (DPPC). Moreover, chitosan was modified with guanidine to form chitosan-guanidine (CG), which not only can improve the encapsulation efficiency of anti-miR-21 oligonucleotides but also effectively capture carbon dioxide (CO2) into the nanoparticle to achieve the ‘nano-bomb’ effect for triggered drug release under the reduced pH in tumors. The two agents (inhibitors of miR-21 and WIP1)-laden nanoparticles can be used to efficiently kill trastuzumab-resistant HER2+ breast cancer cells, leading to a profound reduction of the tumor growth in vivo. These results demonstrate the great potential of the combined treatment of WIP1 and miR-21 inhibitors for the HER2+ breast cancers resistant to anti-HER2-based therapies.
2018-10-03 | GSE119210 | GEO
Project description:Inhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but a significant fraction of HER2-positive (HER2+) breast cancers recur or fail to respond. Anti-HER2 monoclonal antibodies, like trastuzumab or pertuzumab, and ATP active site inhibitors like lapatinib, commonly lack durability because of adaptive changes in the tumor leading to resistance. HER2-directed therapy using clinically relevant drugs (trastuzumab with or without lapatinib or pertuzumab) in a 7-day clinical trial (ClinicalTrials.gov Identifier: NCT01875666, LCCC1214) designed to examine early pharmacodynamic response to antibody-based anti-HER2 therapy showed reduced FOXA1 transcription factor expression was coincident with decreased HER2 and HER3 levels, decreased proliferation gene signatures, and increased immune gene signatures. Patient samples from this trial, when sufficient material was available, were also subjected to kinase enrichment using multiplexed kinase inhibitor bead affinity chromatography and LC-MS/MS. Strongly responsive transcriptional responses observed in a subset of patients corresponded to decreased binding of CDK1 and DDR1 by our proteomic approach. Taken together, our results highlight the importance of the immune response to anti-HER2 antibodies and suggests that inhibiting FOXA1-mediated adaptive responses in combination with HER2 targeting is a potential therapeutic strategy.
2021-04-09 | PXD021865 | Pride
Project description:Purpose: We generated extensive transcriptional and proteomic profiles from a Her2-driven mouse model of breast cancer that closely recapitulates human breast cancer. This report makes these data publicly available in raw and processed forms, as a resource to the community. Importantly, we previously made biospecimens from this same mouse model freely available through a sample repository, so researchers can obtain samples to test biological hypotheses without the need of breeding animals and collecting biospecimens. Experimental design: Twelve datasets are available, encompassing 841 LC-MS/MS experiments (plasma and tissues) and 255 microarray analyses of multiple tissues (thymus, spleen, liver, blood cells, and breast). Cases and controls were rigorously paired to avoid bias. Results: In total, 18,880 unique peptides were identified (PeptideProphet peptide error rate â¤1%), with 3884 and 1659 non-redundant protein groups identified in plasma and tissue datasets, respectively. Sixty-one of these protein groups overlapped between cancer plasma and cancer tissue. Conclusions and clinical relevance: These data are of use for advancing our understanding of cancer biology, for software and quality control tool development, investigations of analytical variation in MS/MS data, and selection of proteotypic peptides for MRM-MS. The availability of these datasets will contribute positively to clinical proteomics. Custom Agilent 44K whole mouse genome expression oligonucleotide microarrays were used to profile breast tumors from three Her2/Neu mice compared to normal breast epithelium from two control mice transgenic for TetO-NeuNT only and littermates of the bitransgenic mice. All samples were laser-capture microdissected and total RNA isolated and amplified prior to hybridization against a reference pool of normal adult mouse tissues.
2010-10-18 | E-GEOD-20280 | biostudies-arrayexpress
Project description:Using high-resolution oligonucleotide arrayCGH, FISH, and RT-PCR we have performed a comprehensive analysis of genomic imbalances, and CRTC1-MAML2 gene fusion status in a series of 28 well characterized mucoepidermoid carcinomas (MECs) with the aims to identify distinct differences in genomic profiles and CRTC1-MAML2 gene fusion status between low- and high-grade MECs. High-resolution aCGH (44K/244K) on fresh frozen and paraffin embedded tissue from 28 well-characterized MECs.
2012-12-31 | E-GEOD-36282 | biostudies-arrayexpress