Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA174999 | ENA |
REPOSITORIES: ENA
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Project description:Cyclin D1b is a splice variant of the cell cycle regulator Cyclin D1 and is known to harbor divergent and highly oncogenic functions in human disease. While Cyclin D1b is induced during disease progression in many cancer types, the mechanisms underlying Cyclin D1b function remain poorly understood. Herein, models of human disease were utilized to resolve the downstream pathways requisite for the pro-tumorigenic functions of Cyclin D1b. Specifically, it was shown that Cyclin D1b modulates the expression of a large transcriptional network that cooperates with AR signaling to enhance tumor cell growth and invasive potential. Notably, Cyclin D1b promoted AR-dependent activation of genes associated with metastatic phenotypes. Further exploration determined that transcriptional induction of SNAI2 (Slug) was essential for Cyclin D1b- mediated proliferative and invasive properties, implicating Slug as a critical driver of disease progression. Importantly, Cyclin D1b expression highly correlated with that of Slug in clinical samples of advanced disease. Further, in vivo analyses provided strong evidence that Slug enhances both tumor growth and homing to distal soft tissues. Collectively, these findings reveal the underpinning mechanisms behind the pro-tumorigenic functions of Cyclin D1b, and demonstrate that the convergence of the Cyclin D1b-AR and Slug pathways results in the activation of processes critical for the promotion of lethal tumor phenotypes. Analysis of transcriptomes under the control of individual D-type cyclin isoforms in the hormone dependent prostate cancer cell line LNCaP in the presence and absence of androgen. LNCaP cells cultured in charcoal dextran treated media were transduced with virus encoding Cyclin D1a, Cyclin D1b, or control GFP for 24 hours in biological triplicate. Cells were then stimulated with either 1nM DHT or 0.01% EtOH (vehicle control) for 16 hours and harvested for RNA
2013-03-31 | E-GEOD-40794 | biostudies-arrayexpress
Project description:Aberrant BAF57 Signaling Facilitates Pro-metastatic Phenotypes
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Project description:Cyclin D1b is a splice variant of the cell cycle regulator Cyclin D1 and is known to harbor divergent and highly oncogenic functions in human disease. While Cyclin D1b is induced during disease progression in many cancer types, the mechanisms underlying Cyclin D1b function remain poorly understood. Herein, models of human disease were utilized to resolve the downstream pathways requisite for the pro-tumorigenic functions of Cyclin D1b. Specifically, it was shown that Cyclin D1b modulates the expression of a large transcriptional network that cooperates with AR signaling to enhance tumor cell growth and invasive potential. Notably, Cyclin D1b promoted AR-dependent activation of genes associated with metastatic phenotypes. Further exploration determined that transcriptional induction of SNAI2 (Slug) was essential for Cyclin D1b- mediated proliferative and invasive properties, implicating Slug as a critical driver of disease progression. Importantly, Cyclin D1b expression highly correlated with that of Slug in clinical samples of advanced disease. Further, in vivo analyses provided strong evidence that Slug enhances both tumor growth and homing to distal soft tissues. Collectively, these findings reveal the underpinning mechanisms behind the pro-tumorigenic functions of Cyclin D1b, and demonstrate that the convergence of the Cyclin D1b-AR and Slug pathways results in the activation of processes critical for the promotion of lethal tumor phenotypes. Analysis of transcriptomes under the control of individual D-type cyclin isoforms in the hormone dependent prostate cancer cell line LNCaP in the presence and absence of androgen.
2013-03-31 | GSE40794 | GEO
Project description:Cancer represents a complex family of diseases, characterized by the uncontrolled malignant growth of a particular cell type and by metastatic dissemination of these transformed cells to secondary sites. The hallmark tumor features emerge as a result of aberrant cellular signaling and pathological gene expression driven by cooperating genetic lesions. Being the convergence points of signaling pathways, transcription factors play crucial roles in cancer. Here, we define a transcription factor network that triggers an abnormal gene expression program promoting malignancy of clonal tumors, generated in Drosophila imaginal disc epithelium by overexpressing oncogenic Ras (RasV12) in a background lacking the tumor suppressor gene scribble (scrib1). We show that the nuclear receptor Ftz-F1 and the ETS-domain transcription factor Ets21c are upregulated in the rasV12scrib1 tumors in response to activated Jun-N-terminal kinase (JNK) signaling. Depletion of either Ftz-F1 or Ets21c improves viability of Drosophila larvae suffering from tumors, and this effect can be further enhanced by simultaneous removal of the Jun-dimerizing partner Fos. We identified Fos as a key mediator of JNK-induced differentiation defects and further show that Ftz-F1 and Fos are required for tumor invasiveness. However, only Ets21c can efficiently substitute for JNK and cooperate with RasV12 to induce invasive tumors that recapitulate hallmarks of malignant rasV12scrib1 tumors including elevated matrix metalloprotease (MMP1) and insulin-like peptide 8 (Dilp8) expression. In conclusion, our study provides functional evidence for a network of cooperating transcription factor that dictates target gene expression and promotes tumor phenotypes in response to aberrant JNK signaling. 20 samples analyzed, 4 control samples
2015-11-04 | E-GEOD-65261 | biostudies-arrayexpress
Project description:FSTL1 promotes cancer cell invasion through pro-invasive and pro-inflammatory pathways
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Project description:Broad-Spectrum Therapeutic Suppression of Metastatic Melanoma Through Nuclear Hormone Receptor Activation
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Project description:Tumor heterogeneity complicates patient treatment and can be due to transitioning of cancer cells across phenotypic cell states. This process is associated with the acquisition of independence from an oncogenic driver, such as the estrogen receptor (ER) in breast cancer, resulting in tumor progression, therapeutic failure and metastatic spread. Here we identify the transcription factor ONECUT2 (OC2) as a lineage plasticity regulator of breast cancer (BC) that suppresses the estrogen axis and promotes luminal to basal transition. OC2 is highly expressed in a substantial subset of hormone receptor negative human BC tumors and is associated with poor clinical outcome, lymph node metastasis and heightened clinical stage. We also show that OC2 is required for cell growth and survival in metastatic BC models and that it can be targeted with a small molecule inhibitor providing a novel therapeutic strategy for patients with OC2 active tumors.
2024-05-23 | GSE242540 | GEO
Project description:Tumor heterogeneity complicates patient treatment and can be due to transitioning of cancer cells across phenotypic cell states. This process is associated with the acquisition of independence from an oncogenic driver, such as the estrogen receptor (ER) in breast cancer, resulting in tumor progression, therapeutic failure and metastatic spread. Here we identify the transcription factor ONECUT2 (OC2) as a lineage plasticity regulator of breast cancer (BC) that suppresses the estrogen axis and promotes luminal to basal transition. OC2 is highly expressed in a substantial subset of hormone receptor negative human BC tumors and is associated with poor clinical outcome, lymph node metastasis and heightened clinical stage. We also show that OC2 is required for cell growth and survival in metastatic BC models and that it can be targeted with a small molecule inhibitor providing a novel therapeutic strategy for patients with OC2 active tumors.
2024-05-23 | GSE242539 | GEO
Project description:Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers
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Project description:The promyelocytic leukemia (PML) protein organizes nuclear aggregates known as PML nuclear bodies (PML-NBs), where many transcription factors and transcriptional regulators converge to be regulated. Specific associations of PML and PML-NBs with chromatin are described in different cell types, further implicating PML in transcriptional regulation. However, a complete understanding of the functional consequences of PML association to DNA in a cellular context where it regulates relevant phenotypes is still lacking.We examined the role of PML in chromatin association and transcription in triple-negative breast cancer (TNBC), a pathological condition where PML exerts important oncogenic functions. We find that PML associates discontinuously with large heterochromatic PML-associated domains (PADs) that contain gene-rich euchromatic sub-domains locally depleted of PML. PML promotes heterochromatic organization in PADs and expression of pro-metastatic genes embedded in these sub-domains. Importantly, this occurs outside PML-NBs, suggesting that nucleoplasmic PML exerts a cell type-relevant function of transcriptional regulation. PML also plays an indirect regulatory function in TBNC cells by promoting the expression of pro-metastatic genes outside PADs.Our findings demonstrate that PML is an important transcriptional regulator of metastasis and pro-oncogenic metagenes in TNBC cells, via distinct molecular activities that include indirect transcriptional regulation and direct epigenetic organization of heterochromatin domains that embed regions of localized transcriptional activity.
2023-09-11 | GSE226111 | GEO