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Loss of Fbxw7 triggers mammary tumorigenesis associated with E2F/c-Myc activation and Trp53 mutation

ABSTRACT: Fbw7 is a tumor suppressor protein that regulates the degradation of a multitude of oncogenic substrates, such as c-Jun, c-Myc, Notch1 intracellular domain, and cyclin E. Loss of FBXW7 expression is relatively common in breast cancer. Despite this, the effect of FBXW7 loss on breast tumorigenesis has not been examined. We demonstrate here that loss of FBXW7 is sufficient for breast tumorigenesis. Many of Fbw7’s substrates are transcription factors or are closely linked to transcription factor pathways. As loss of Fbw7 results in upregulation of multiple substrates, we set out to determine which, if any of these transcription factor pathways predominate early after Fbw7 loss and after tumorigenesis. To address this, we employed genome-wide RNA sequencing to examine transcription factor pathway alterations early after FBXW7 loss in non-tumor breast epithelial cells as well as after prolonged FBXW7 loss, in tumor samples. We demonstrate an early upregulation of E2F and c-Myc pathways that is reinforced upon tumorigenesis. These findings suggest E2F and c-Myc as important targetable pathways in Fbw7 low breast cancer patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE144690 | GEO | 2020/07/15

REPOSITORIES: GEO

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Loss of Fbxw7 triggers mammary tumorigenesis associated with E2F/c-Myc activation and Trp53 mutation

Project description:Loss of Fbxw7 triggers mammary tumorigenesis associated with E2F/c-Myc activation and Trp53 mutation

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Project description:Ubiquitination is a post-translational mechanism of control of diverse cellular processes. We focus here on the ubiquitin ligase Fbw7, a recently identified hematopoietic tumor suppressor that can target for degradation several important oncogenes including Notch1, c-Myc and cyclin E. We have generated conditional Fbw7 knock-out animals and inactivated the gene in hematopoietic stem cells (HSC) and their differentiated progeny. Deletion of Fbw7 specifically and rapidly affects the HSC compartment in a cell-autonomous manner. Fbw7-/- HSCs show defective maintenance of quiescence, leading to impaired self-renewal and a severe loss of competitive repopulating capacity. Furthermore, Fbw7-/- HSC are unable to colonize the thymus leading to a profound depletion of T cell progenitors. Deletion of Fbw7 in bone marrow stem cells and progenitors leads to the stabilization of c-Myc, a transcription factor previously implicated in HSC self-renewal. On the other hand, neither Notch1 nor cyclin E are stabilized in the bone marrow of Fbw7 deficient mice. Genome-wide transcriptome studies of Fbw7-/- HSC and hematopoietic progenitors indicate that Fbw7 controls, through the regulation of HSC cell cycle entry, the global transcriptional âsignatureâ that is associated with the quiescent, self-renewing HSC phenotype. Transcriptional consequences of inactivating Fbw7 in LKS cells. Experiment Overall Design: Four samples were analyzed: wild-type (WT) control and Fbw7-deficient (FBW7) Lin-ckit+Sca1+ (LSK) cells, as well as Lin-ckit+Sca1- myeloid progenitor (MP) cells, which served as a control for LSK-enriched/specific genes. Total bone marrow cells were pooled from three WT and three FBW7 mice before sorting LSK and MP populations.

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Gene expression data from SW1990 cells stably expressing Fbw7

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2015-12-31 | E-GEOD-76443 | biostudies-arrayexpress

Control of hematopoietic stem cell quiescence by the E3 Ubiquitin Ligase Fbw7

Project description:Ubiquitination is a post-translational mechanism of control of diverse cellular processes. We focus here on the ubiquitin ligase Fbw7, a recently identified hematopoietic tumor suppressor that can target for degradation several important oncogenes including Notch1, c-Myc and cyclin E. We have generated conditional Fbw7 knock-out animals and inactivated the gene in hematopoietic stem cells (HSC) and their differentiated progeny. Deletion of Fbw7 specifically and rapidly affects the HSC compartment in a cell-autonomous manner. Fbw7-/- HSCs show defective maintenance of quiescence, leading to impaired self-renewal and a severe loss of competitive repopulating capacity. Furthermore, Fbw7-/- HSC are unable to colonize the thymus leading to a profound depletion of T cell progenitors. Deletion of Fbw7 in bone marrow stem cells and progenitors leads to the stabilization of c-Myc, a transcription factor previously implicated in HSC self-renewal. On the other hand, neither Notch1 nor cyclin E are stabilized in the bone marrow of Fbw7 deficient mice. Genome-wide transcriptome studies of Fbw7-/- HSC and hematopoietic progenitors indicate that Fbw7 controls, through the regulation of HSC cell cycle entry, the global transcriptional “signature” that is associated with the quiescent, self-renewing HSC phenotype. Transcriptional consequences of inactivating Fbw7 in LKS cells. Keywords: cell type comparison

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