Pan-cancer molecular analysis of the RB-pathway
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA606752 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11088914.fastq.gz | Fastqsanger.gz | |||
| SRR11088915.fastq.gz | Fastqsanger.gz | |||
| SRR11088916.fastq.gz | Fastqsanger.gz | |||
| SRR11088917.fastq.gz | Fastqsanger.gz | |||
| SRR11088918.fastq.gz | Fastqsanger.gz |
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Project description:The retinoblastoma tumor suppressor (RB1) plays a critical role in coordinating multiple pathways that impact on tumor initiation, disease progression, and therapeutic responses. Here we interrogated the TCGA pan-cancer data collection to probe fundamental molecular features associated with the RB-pathway across 31 tumor-types. While the RB-pathway has been purported to exhibit multiple mutually exclusive events, only RB1 is mutually exclusive with multiple genetic events that deregulate CDK4/6 activity. Using an isogenic ER+ breast cancer model with targeted RB1 deletion, we identified gene expression features that link CDK4/6 activity and RB-dependency (CDK4/6-RB integrated signature). This gene expression signature is associated with prognosis across a spectrum of tumors that exhibit average lower signature value indicative of more indolent diseases. Single copy loss on chromosome 13q encompassing the RB1 locus is prevalent in many cancers, and is associated with reduced expression of multiple genes on 13q including RB1, and inversely related to the CDK4/6-RB integrated signature supporting a genetic cause/effect relationship. To probe the broader implications on tumor biology, we investigated genes that are positively and inversely correlated with the CDK4/6-RB integrated signature. This approach defined tumor-specific pathways that could represent new therapeutic vulnerabilities associated with RB-pathway activity.
2020-03-02 | GSE145316 | GEO
Project description:The retinoblastoma tumor suppressor gene (RB1) plays a critical role in coordinating multiple pathways that impact cancer initiation, disease progression, and therapeutic responses. Here we probed molecular features associated with the RB-pathway across 31 tumor-types. While the RB-pathway has been purported to exhibit multiple mutually exclusive genetic events, only RB1 alteration is mutually exclusive with deregulation of CDK4/6 activity. An ER+ breast cancer model with targeted RB1 deletion was used to identify signatures of CDK4/6 activity and RB-dependency (CDK4/6-RB integrated signature). This signature was prognostic in tumor-types with gene expression features indicative of slower growth. Single copy loss on chromosome 13q encompassing the RB1 locus is prevalent in many cancers, yielding reduced expression of multiple genes in cis, and is inversely related to the CDK4/6-RB integrated signature supporting a cause-effect relationship. Genes that are positively and inversely correlated with the CDK4/6-RB integrated signature define new tumor-specific pathways associated with RB-pathway activity.
| S-EPMC7118159 | biostudies-literature
Project description:Mutations in cancer are due in part to DNA cytosine deamination by APOBEC3B (A3B). While low in healthy tissues, A3B expression and activity are elevated in tumors and further increase in metastases. However, molecular mechanisms responsible for A3B transcriptional regulation are poorly understood. Here, we address whether the RB/E2F pathway, which is often dysregulated in breast cancer, is a molecular trigger of A3B overexpression. First, an A3B promoter-driven luciferase reporter was used to demonstrate reporter activation by disruption of only one out of five predicted E2F binding sites. Second, A3B-luciferase reporter activation was also triggered by expressing the BK polyomavirus T-antigen, which inactivates RB and thereby alleviates repression of E2F regulated genes. Importantly, A3B-luciferase reporter induction by BK polyomavirus T-antigen could not be further increased by mutating the functional E2F binding site. Third, both CRISPR disruption and targeted base substitutions in the endogenous E2F binding site caused strong A3B upregulation and confirmed importance of this regulatory element. Fourth, proteomics experiments showed that members of the DREAM and PRC1.6-complexes including multiple E2F family members are able to bind to wild-type but not E2F mutant promoter sequences. Finally, a combination of genetic and biochemical studies implicated E2F4 and E2F6 in endogenous A3B gene repression. Altogether, our studies demonstrate that A3B expression is suppressed in normal cells by the RB/E2F axis and that viral or mutational disruption of this pathway causes overexpression of this DNA deaminase in cancer and contributes mutational fuel to tumor evolution.
2020-10-19 | PXD020473 | Pride
Project description:Breast cancer is a highly heterogeneous disease that is categorized into distinct tumor subtypes based on specific molecular attributes, which ultimately influence therapeutic options. Unlike ER+ and/or HER2+ cancers that are subject to specific targeted therapies, triple negative breast cancers (TNBCs) do not express these receptors, which leaves patients with limited treatment options. Thus, significant focus has been placed on identifying molecular attributes of basal-like disease that could be used to develop and/or direct novel treatment regimens. Activation of MYC signaling and inactivation of the RB-pathway are frequent events in many types of human cancers. These pathways influence many biological processes, such as cell proliferation, that contribute to the aggressiveness and therapeutic response of tumors. The current study examines the interaction of the MYC and RB pathways in mammary epithelial cell tumorigenesis. Mouse mammary epithelial cells were isolated and sub-cultured. Adenoviral expression of Cre-recombinase was used to delete the RB and/or p53 genes, and retrovirus was used to achieve MYC overexpression (OE). Proliferating cells were harvested for each condition, and RNA was isolated for analyses.
2013-08-01 | E-GEOD-40545 | biostudies-arrayexpress
Project description:Proliferative control in cancer cells is frequently disrupted by mutations in the RB-pathway. Paradoxically, RB1 mutations can arise late in tumorigenesis in cancer cells whose RB-pathway is already compromised by another mutation. In this study, we present evidence for increased DNA damage in CDKN2A deleted cancer cells when RB1 mutations are induced. We created isogenic RB1 wild type, heterozygous, and null genotypes. Cells with even one mutant copy of RB1 have increased basal levels of DNA damage and increased mitotic errors. Elevated levels of reactive oxygen species as well as impaired homologous recombination repair underlie this DNA damage. When xenografted into immune compromised mice RB1 mutant cells exhibit an elevated propensity to seed new tumors in recipient lungs. This study offers evidence that late arising RB1 mutations can facilitate genome instability and cancer progression that are beyond the pre-existing proliferative control deficit.
2019-06-18 | GSE125379 | GEO
Project description:Protein tyrosine phosphatase 1B (PTP1B) plays a key role in developing different types of cancer. However, the molecular mechanism underlying this effect is unclear. To identify possible molecular targets of PTP1B that mediate its positive role in tumorigenesis, we undertook a SILAC-based phosphoproteomic approach, which allowed us to identify the Cyclin-dependent kinase 3 (Cdk3) as a novel PTP1B substrate. Molecular docking studies revealed stable interactions between the PTP1B catalytic domain and Cdk3. In addition, we observed that PTP1B dephosphorylates Cdk3 at Tyrosine residue 15 in vitro and interacts with it in the nucleus and cytoplasm of human glioblastoma (GB) cells. Finally, we found that the pharmacological inhibition of PTP1B or its depletion with siRNA leads to cell cycle arrest with the diminished activity of Cdk3, the consequent hypophosphorylation of Rb, and the down-regulation of E2F and its target genes Cdk1, Cyclin A, and Cyclin E1. These data delineate a novel signaling pathway from PTP1B to Cdk3 required for efficient cell cycle progression in an Rb-E2F dependent manner in human GB cells and suggest new therapeutic strategies for treating these tumors.
2023-12-05 | PXD046000 | Pride
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Project description:The retinoblastoma tumor suppressor (RB1) plays a critical role in coordinating multiple pathways that impact on tumor initiation, disease progression, and therapeutic responses. Here we interrogated the effect of CDK4/6 inhibitor in combination with mTOR inhibtor. Also, we interrogtaed the efffect of AURK and WEE1 inhibition in ER+ breast cacner models While the RB-pathway has been purported to exhibit multiple mutually exclusive events, only RB1 is mutually exclusive with multiple genetic events that deregulate CDK4/6 activity. Using an isogenic ER+ breast cancer model with targeted RB1 deletion, we identified gene expression features that link CDK4/6 activity and RB-dependency (CDK4/6-RB integrated signature). We also investigated the role of RB on apoptotic pathway. Single copy loss on chromosome 13q encompassing the RB1 locus is prevalent in many cancers, and is associated with reduced expression of multiple genes on 13q including RB1, and inversely related to the CDK4/6-RB integrated signature supporting a genetic cause/effect relationship. To probe the broader implications on tumor biology, we investigated genes that are positively and inversely correlated with the CDK4/6-RB integrated signature. This approach defined tumor-specific pathways that could represent new therapeutic vulnerabilities associated with RB-pathway activity.
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