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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Affymetrix SNP array data for breast cancer samples

ABSTRACT: Chromosomal structural mutations play an important role in determining the transcriptional landscape of human breast cancers. We determined that pro-oncogenic and anti-oncogenic genes are clustered throughout the genome and that these clusters coincide with regions of segmental amplification and deletion. We constructed detailed structural mutation maps of representative breast cancers and found that tandem duplications appear to nucleate regions for amplification. Subsequent rearrangements link distant pro-oncogenic elements for co-amplification, and are associated with loss of tumor suppressors. We show that genes engaged in co-amplifications or conjoint deletions on 17q and 8q have pro-growth effects that are additive in nature. Our results suggest structural mutations efficiently orchestrate the gain and loss of cancer gene cassettes that engage many oncogenic pathways simultaneously. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from fresh-frozen breast tumors with >80% tumor cell content and their paired peripheral blood samples. Copy number analysis of the SNP arrays was done using the copy number pipeline implemented into Partek software version 6.5

ORGANISM(S): Homo sapiens

SUBMITTER: Edison Liu

PROVIDER: E-GEOD-48377 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Affymetrix SNP array data for breast cancer samples

Project description:Chromosomal structural mutations play an important role in determining the transcriptional landscape of human breast cancers. We determined that pro-oncogenic and anti-oncogenic genes are clustered throughout the genome and that these clusters coincide with regions of segmental amplification and deletion. We constructed detailed structural mutation maps of representative breast cancers and found that tandem duplications appear to nucleate regions for amplification. Subsequent rearrangements link distant pro-oncogenic elements for co-amplification, and are associated with loss of tumor suppressors. We show that genes engaged in co-amplifications or conjoint deletions on 17q and 8q have pro-growth effects that are additive in nature. Our results suggest structural mutations efficiently orchestrate the gain and loss of cancer gene cassettes that engage many oncogenic pathways simultaneously.

2013-06-29 | GSE48377 | GEO

Chromosome as oncogenic organizer: functional consequences of structural mutations in breast cancer (RNA-Seq)

Project description:Chromosomal structural mutations play an important role in determining the transcriptional landscape of human breast cancers. To assess the nature of these structural mutations, we analyzed a representative sampling of the major types of breast tumor samples for detailed structural mutations using paired-end tag sequencing of long-insert genomic DNA (DNA-PET) with matched transcriptome ascertainment by RNA-seq. Compared with other structural mutations, tandem duplications are enriched around partners of fusion transcripts and demarcate regions of high gene expression. Moreover tandem duplications appear to be early events in tumor evolution by facilitating subsequent downstream amplification and deletion of important adjacent cancer associated genes. In a detailed reconstruction of events in chr17, we found large unpaired-inversions connect a duplicated ERBB2 with neighboring 17q21.3 amplicons while simultaneously deleting the intervening BRCA1 tumor suppressor locus. Using siRNAs in breast cancer cell lines, we showed that the 17q21.3 amplicon harbored a significant number of weak oncogenes that appeared consistently co-amplified in primary tumors. Down-regulation of BRCA1 expression augmented the cell proliferation in human normal mammary epithelial cells. Finally, using in silico approaches, we determined that genes whose expression in breast tumors are associated with either poor or good clinical prognosis appear clustered together in segments of frequent amplification or deletion, suggesting that structural abnormalities induce the loss or gain of blocks of adjacent genes with oncogenic or growth suppressor function. These analyses suggest that structural mutations efficiently orchestrate the gain and loss of cancer gene cassettes that engage many oncogenic pathways simultaneously. RNA sequencing of four primary breast cancer RNA samples (SOLiD, Applied Biosystems).

2014-07-01 | E-GEOD-57914 | biostudies-arrayexpress

Affymetrix SNP array data for EZH2 mediated gene copy number change in breast tumor initiating cells

Project description:EZH2 is shown to be involved in regulation of DNA damage repair which may contribute to development of breast tumor initiating cells. To identify genomic aberrations regulated by EZH2 expression, we performed genome wide copy number variation analysis in breast tumor initiating cells expressing EZH2 compared to the vector control. This finding suggests EZH2 contributes to oncogenic amplification in breast tumor initiating cells. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from primary breast tumor initiating cells infected with EZH2 or Vector control constructs Copy number variation analysis of Affymetrix SNP 6.0 arrays was performed and compared between EZH2 and Vector control infected groups

2010-09-17 | E-GEOD-24144 | biostudies-arrayexpress

Chromosome as oncogenic organizer: functional consequences of structural mutations in breast cancer (RNA-Seq)

2014-07-01 | GSE57914 | GEO

Structural mechanism for inhibition of PP2A-B56 and oncogenicity by CIP2A

Project description:Abstract The protein phosphatase 2A (PP2A) heterotrimer PP2A-B56 is a human tumor suppressor. However, the molecular mechanisms inhibiting PP2A-B56in cancer are poorly understood. Here, we report molecular level details and structural mechanism of PP2A-B56inhibition by an oncoprotein CIP2A. Upon direct binding to PP2A-B56 trimer, CIP2A replaces PP2A-A subunit and thereby hijacks both the B56 and the catalytic PP2Ac subunit to form a CIP2A-B56-PP2Ac pseudotrimer. Further, CIP2A competes with B56 substrate binding by blocking the LxxIxE-motif substrate binding pocket on B56. Relevant to oncogenic activity of CIP2A across human cancers, the N-terminal head domain-mediated interaction with B56 stabilizes CIP2A protein. Functionally, CRISPR/Cas9-mediated single amino acid mutagenesis of the head domain blunted MYC expression and MEK phosphorylation, and abrogated triple-negative breast cancer in vivo tumor growth. Collectively, we discover a unique multi-step “hijack and mute” mechanism of protein complex regulation inhibiting tumor suppressor PP2A-B56. Further, the results unfold single structural determinant for CIP2A´s oncogenic activity, potentially facilitating therapeutic modulation of CIP2A in cancer and other diseases.

2023-03-11 | PXD030297 | Pride

Oncogene-like induction of cellular invasion from centrosome amplification

Project description:Centrosome amplification has long been recognized as a feature of human tumors, however its role in tumorigenesis remains unclear. Centrosome amplification is poorly tolerated by non-transformed cells, and, in the absence of selection, extra centrosomes are spontaneously lost. Thus, the high frequency of centrosome amplification, particularly in more aggressive tumors, raises the possibility that extra centrosomes could, in some contexts, confer advantageous characteristics that promote tumor progression. Using a three-dimensional model system and other approaches to culture human mammary epithelial cells, we find that centrosome amplification triggers cell invasion. This invasive behavior is similar to that induced by overexpression of the breast cancer oncogene ErbB2 and indeed enhances invasiveness triggered by ErbB2. We show that, through increased centrosomal microtubule nucleation, centrosome amplification increases Rac1 activity, which disrupts normal cell-cell adhesion and promotes invasion. These findings demonstrate that centrosome amplification, a structural alteration of the cytoskeleton, can promote features of malignant transformation. genome-wide human SNP 6.0 arrays from Affymetrix was used to determine the copy number changes of MCF10A cells with extra centrosomes or depleted of MCAK after grown 4 days in 3-D cultures

2014-03-01 | E-GEOD-55042 | biostudies-arrayexpress

Identification of novel gene amplification events in breast cancer

Project description:To identify novel gene amplification events that may contribute to breast cancer progression, we examined copy number variation in 161 primary breast cancer samples using the Affymetrix 250K_Nsp and 250K_Sty microarrays or the Affymetrix SNP5.0 microarray. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from primary breast cancer samples. Copy number variations were determined from probeset signal intensities.

2010-06-23 | E-GEOD-16619 | biostudies-arrayexpress

Homo sapiens

Project description:Chromosome as oncogenic organizer: functional consequences of focal amplification shaped by structural mutations in breast cancer

| PRJNA234462 | ENA

Global transcriptional analysis identifies a novel role for SOX4 in tumor-induced angiogenesis

Project description:The expression of the transcription factor SOX4 is increased in many human cancers, however, the pro-oncogenic capacity of SOX4 can vary greatly depending on the tumor-type. Both the contextual nature and the mechanisms underlying the pro-oncogenic SOX4 response remain unexplored. Here, we demonstrate that in mammary tumorigenesis, the SOX4 transcriptional network is dictated by the epigenome and is enriched for pro-angiogenic processes. We show that SOX4 directly regulates endothelin-1 (ET-1) expression and thereby promotes tumor-induced angiogenesis both in vitro and in vivo. Furthermore, in breast tumors, SOX4 expression correlates with blood vessel density and size, and predicts poor-prognosis in breast cancer patients. Our data provide novel mechanistic insights into context-dependent SOX4 target gene selection, and uncover a novel pro-oncogenic role by promoting tumor-induced angiogenesis. These findings establish a key role for SOX4 in promoting metastasis through exploiting diverse pro-tumorigenic pathways.

2020-01-01 | GSE99256 | GEO

c-Myc/BMI1 axis is essential for SETDB1-mediated breast tumorigenesis

Project description:Copy number gain/amplification of SETDB1 has been found in several human cancers, but the detailed oncogenic mechanism(s) of SETDB1 contributing to breast cancer remains largely unexplored. In this project, we analyzed the transcriptome of human breast cancer cell lines (MDA-MB-231 and MDA-MB-453) upon silencing of SETDB1 to explore the potential mechanism(s) underlying SETDB1 promoted breast cancer. In MDA-MB-231 cells, SETDB1 was silenced by shRNA-1. In MDA-MB-453 cells, SETDB1 was reduced by shRNA-3.

2018-05-01 | GSE108656 | GEO

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