Rnf8 loss promotes breast carcinogenesis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE76075 | GEO | 2017/01/01
SECONDARY ACCESSION(S): PRJNA306167
REPOSITORIES: GEO
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Project description:Breast cancer linked with BRCA1/2 mutations commonly recur and resist current therapies, including PARP inhibitors. Given the lack of effective targeted therapies for BRCA1-mutant cancers, we sought to identify novel targets to selectively kill these cancers. Here, we report that loss of RNF8 significantly protects Brca1-mutant mice against mammary tumorigenesis. RNF8 deficiency in human BRCA1-mutant breast cancer cells was found to promote R-loop accumulation and replication fork instability, leading to increased DNA damage, senescence, and synthetic lethality. Mechanistically, RNF8 interacts with XRN2, which is crucial for transcription termination and R-loop resolution. We report that RNF8 ubiquitylates XRN2 to facilitate its recruitment to R-loop-prone genomic loci and that RNF8 deficiency in BRCA1-mutant breast cancer cells decreases XRN2 occupancy at R-loop-prone sites, thereby promoting R-loop accumulation, transcription-replication collisions, excessive genomic instability, and cancer cell death. Collectively, our work identifies a synthetic lethal interaction between RNF8 and BRCA1, which is mediated by a pathological accumulation of R-loops.
2023-09-14 | GSE202723 | GEO
Project description:SUMMARY: Basal breast cancer has been associated with mutations in a number of specific tumor suppressor genes, however, the mechanism by which these tumors express a basal lineage remains unknown. Notch signaling suppresses mammary stem cell (MaSC) self-renewal, while promoting luminal cell fate specification. Here we show that Lfng, a sugar transferase that facilitates Notch activation, suppresses mammary stem/bipotent progenitor cell proliferation. Targeted deletion of Lfng in mammary epithelium induces basal tumors with reduced expression of Notch targets, amplification of the Met/Caveolin gene locus, and elevated Met and Igf-1R signaling. Human basal breast cancer, a disease associated with elevated MET receptor signaling and Caveolin protein, express low levels of LFNG. Thus, reduced LFNG expression cooperates with a Met/ Caveolin amplicon to promote basal breast disease. SIGNIFICANCE: Anti-Notch therapy is currently being tested for efficacy against basal-like breast cancer in humans. Here we report that LFNG, which controls Notch receptor activation, is consistently expressed at a low level in basal tumors and that deletion of this gene in the mouse mammary gland reduces Notch signaling, increases proliferation and induces basal mammary tumors in cooperation with amplification of the Met/Caveolin gene locus. These mutations interact to promote basal gene expression by decreasing Notch pathway activation, as well as to enhance Met and Igf-1R signaling. These pathways can be targeted at multiple levels in humans harboring basal breast cancer with amplification of MET and CAV1/2 32 array samples
2012-05-29 | E-GEOD-28712 | biostudies-arrayexpress
Project description:SUMMARY: Basal breast cancer has been associated with mutations in a number of specific tumor suppressor genes, however, the mechanism by which these tumors express a basal lineage remains unknown. Notch signaling suppresses mammary stem cell (MaSC) self-renewal, while promoting luminal cell fate specification. Here we show that Lfng, a sugar transferase that facilitates Notch activation, suppresses mammary stem/bipotent progenitor cell proliferation. Targeted deletion of Lfng in mammary epithelium induces basal tumors with reduced expression of Notch targets, amplification of the Met/Caveolin gene locus, and elevated Met and Igf-1R signaling. Human basal breast cancer, a disease associated with elevated MET receptor signaling and Caveolin protein, express low levels of LFNG. Thus, reduced LFNG expression cooperates with a Met/ Caveolin amplicon to promote basal breast disease. SIGNIFICANCE: Anti-Notch therapy is currently being tested for efficacy against basal-like breast cancer in humans. Here we report that LFNG, which controls Notch receptor activation, is consistently expressed at a low level in basal tumors and that deletion of this gene in the mouse mammary gland reduces Notch signaling, increases proliferation and induces basal mammary tumors in cooperation with amplification of the Met/Caveolin gene locus. These mutations interact to promote basal gene expression by decreasing Notch pathway activation, as well as to enhance Met and Igf-1R signaling. These pathways can be targeted at multiple levels in humans harboring basal breast cancer with amplification of MET and CAV1/2
2012-05-30 | GSE28712 | GEO
Project description:RNF8 is downregulated in glioblastoma and low RNF8 expression correlates with poor patient prognosis. Overexpression (OE) of RNF8 in glioblastoma stem cell (GSC) impairs its proliferation and tumorigenicity, and the anti-cancer effects of RNF8 are dependent on both its FHA and RING domains. Paradoxically, transcriptomic analysis of RNF8 OE GSC reveals cell cycle as the top upregulated pathway. Mechanistically, RNF8 interacts with the mitotic checkpoint protein MAD2 in a RING domain-dependent manner to induce spindle assembly checkpoint (SAC) activation. RNF8 OE GSC displays increase level of aneuploidy and micronuclei formation, suggesting that RNF8 promotes chromosomal instability (CIN) in GSC through persistent SAC activation.
2022-12-10 | GSE190638 | GEO
Project description:The estrogen receptor alpha (ERa) drives the growth of two-thirds of all breast cancers. Endocrine therapy impinges on estrogen-induced ERa activation to block tumor growth. However, half of ERa-positive breast cancers are tolerant or acquire endocrine therapy resistance. Here we demonstrate that breast cancer cells undergo genome-wide reprogramming of their chromatin landscape, defined by epigenomic maps and chromatin openness, as they acquire resistance to endocrine therapy. This reveals a role for the Notch pathway while excluding classical ERa signaling. In agreement, blocking Notch signaling, using gamma-secretase inhibitors, or targeting its downstream gene PBX1 abrogates growth of endocrine therapy-resistant breast cancer cells. Moreover Notch signaling through PBX1 directs a transcriptional program predictive of tumor outcome and endocrine therapy response. Comparing histone modifications (H3K4me2 and H3K36me3), chromatin openness (FAIRE) and PBX1 binding between endocrine therapy sensitive MCF7 and resistant MCF7-LTED cells.
2013-05-01 | E-GEOD-37323 | biostudies-arrayexpress
Project description:The dire need for more effective treatments for clinically aggressive breast cancers has motivated intensive investigations into their cellular and molecular etiology. Breast cancers that are “triple-negative” for the clinical markers, ESR1, PGR, and HER2, typically belong to the Basal-like molecular subtype. Defective Rb, p53, and Brca1 pathways are each associated with triple-negative and Basal-like subtypes. Our mouse genetic studies demonstrate that concomitant inactivation of all three pathways in mammary epithelium has an additive effect on tumor latency, and predisposes highly penetrant, metastatic, adenocarcinomas. These tumors are poorly differentiated with histologic features that are common among human Brca1-mutated tumors, including heterogeneous morphology, metaplasia, and necrosis. Transcriptomic analyses demonstrated that the tumors shared attributes of both Basal-like and Claudin-low signatures, two molecular subtypes encompassed by the broader triple-negative category defined by clinical markers. Ex vivo tumorsphere formation, which was suppressed by Notch and Wnt pathway inhibition, and tumor antigen profiles and are consistent with enrichment of stem-like and luminal progenitor cells among these tumors. These studies establish a novel mouse model of malignant breast cancer based on events in the human disease and underscore the non-reciprocal requirements of three canonical tumor suppressor pathways in breast cancer evolution. Morphogenetic pathways may provide additional avenues for targeted therapeutic intervention. Gene expression analysis of mouse mammary tumors with perturbation of Rb family pathways, p53, and/or Brca1 are compared to other mouse model tumors (n=152)
2011-12-17 | E-GEOD-34479 | biostudies-arrayexpress
Project description:Luminal to basal transition in mammary gland is accompanied by the changes of epithelial cell lineage plasticity, however, the underlying mechanism remains elusive. Here, we demonstrated that loss of the scaffold protein FRMD3 in breast cancer predicts poor outcomes. Knockout of Frmd3 inhibits mammary gland lineage development and induces mammary epithelium cells (MECs) stemness, and later on emerge of TNBC. Loss of Frmd3 in PyMT mice results in luminal to basal phenotype transition. Single- MEC mRNA sequencing analysis indicated that knockout of Frmd3 corresponds to inhibition of Notch signaling pathway. Mechanistically, FRMD3 assists Dishevelled-2 degradation via enhancing its interaction with the deubiquitinase USP9x. FRMD3 also interrupts the interaction of Dishevelled-2 with CK1, FOXK1, FOXK2 and NICD, causing a decrease in Dishevelled-2 phosphorylation, entry into the nucleus and impairing the Notch-dependent luminal epithelial lineage plasticity in MECs respectively. Taken together, FRMD3 is a tumor suppressor and an endogenous activator of the Notch signaling pathway that regulates mammary epithelial cell lineage plasticity.
2024-07-10 | GSE252083 | GEO
Project description:Notch signaling is frequently hyperactivated in breast cancer, but how the enhanced signaling contributes to the tumor process is less well understood. In this report, we identify the proinflammatory cytokine interleukin-6 (IL-6) as a novel Notch target in breast tumor cells. Enhanced Notch signaling upregulated IL-6 expression at the transcriptional level, leading to activation of autocrine and paracrine JAK/STAT signaling. IL-6 upregulation was mediated by non-canonical Notch signaling, as it could be effectuated by a cytoplasmically localized Notch intracellular domain and was independent on the DNA-binding protein CSL. Instead, Notch-mediated IL-6 upregulation was controlled by two other factors: IKKβ, a protein in the NF-kB signaling cascade, and p53. Activation of IL-6 by Notch required IKKβ function, but interestingly, did not engage canonical NF-κB signaling, in contrast to IL-6 activation by inflammatory agents such as tumor necrosis factor, which requires canonical NF-κB signaling. With regard to p53 status, IL-6 expression was upregulated by Notch when p53 was mutated or lost, but restoring wildtype 53 into p53-mutated or -deficient cells abrogated the IL-6 upregulation. Furthermore, Notch-induced genome-wide transcriptomes from p53 wildtype and -mutated breast tumor cell lines differed extensively, and in a subset of genes upregulated by Notch in a p53-mutant cell line, upregulation was reduced by wildtype p53. In conclusion, we identify IL-6 as a novel non-canonical Notch target gene, and reveal roles for p53 and IKKβ in non-canonical Notch signaling in breast cancer and in the generation of cell context-dependent diversity in the Notch signaling output. 30 microarray samples consisting of MCF7 (ER+, wild-type p53, luminal type B breast cancer) and MDA-MB-231 (ER-, mutated p53, basal breast cancer) cells cultured on immobilized 1 μg/ml JAGGED1-Fc or 1 μg/ml DLL4-Fc or 1 μg/ml Fc control with or without 5 μM DAPT for 6 hours in 3 biological replicates.
2012-06-29 | E-GEOD-36051 | biostudies-arrayexpress
Project description:The estrogen receptor alpha (ERa) drives the growth of two-thirds of all breast cancers. Endocrine therapy impinges on estrogen-induced ERa activation to block tumor growth. However, half of ERa-positive breast cancers are tolerant or acquire endocrine therapy resistance. Here we demonstrate that breast cancer cells undergo genome-wide reprogramming of their chromatin landscape, defined by epigenomic maps and chromatin openness, as they acquire resistance to endocrine therapy. This reveals a role for the Notch pathway while excluding classical ERa signaling. In agreement, blocking Notch signaling, using gamma-secretase inhibitors, or targeting its downstream gene PBX1 abrogates growth of endocrine therapy-resistant breast cancer cells. Moreover Notch signaling through PBX1 directs a transcriptional program predictive of tumor outcome and endocrine therapy response.
2013-05-01 | GSE37323 | GEO
Project description:Breast cancer is one of the leading causes of cancer-related mortality in women. NOTCH signaling is a well conserved pathway which not only plays critical roles in normal development, but also in cancer progression. One of the Notch ligand, JAGGED1 is overexpressed in about 30% of breast cancer patients. However, the role of JAGGED1 in breast tumorigenesis has not been rigorously examined. By utilizing genetic engineered mouse models of mammary specific Jagged1 expression or knockout, we discover that Jagged1 promotes tumorigenesis in multiple spontaneous mammary tumor models. Jagged1 expression leads to increased infiltration of tumor associated macrophages and decreased presentation of T cells within tumor microenvironment. Depletion of macrophages or T cells by neutralizing antibodies diminishes the tumor-promoting effect caused by Jagged1. Mechanistically, Jagged1 activates Notch signaling in tumor cells, leads to increased expression and secretion of multiple cytokines, including IL-6 and WISP. These cytokines help recruit macrophages into the tumor microenvironment. Macrophages crosstalk with infiltrated T cells and inhibit their cytotoxic killing on tumor cells. In triple negative breast cancer patient samples, high expression level of JAGGED1 correlates with increased macrophage infiltration and decreased T cell infiltration within tumor tissues. JAGGED1 also promotes tumor progression in several other solid cancer types, including melanoma, and colon cancer in a T cell dependent manner. Co-administration of immune checkpoint inhibitor, PD-1 antibody with gamma-secretase inhibitor (GSI) significantly inhibits tumor growth. These findings identify a unique oncogenic crosstalk between tumor derived JAGGED1, Macrophages, and T cells to promote tumor progression.
2022-03-08 | GSE161769 | GEO