WNT11 is a novel ligand for ROR2 in human breast cancer
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PROVIDER: PRJNA679735 | ENA |
REPOSITORIES: ENA
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Project description:Breast cancer is the most common cancer in women with more than two million new cases diagnosed in 2018. Patients frequently develop metastases in the course of their disease which limit survival due to the lack of a curative treatment. One signaling pathway that is frequently involved in cancer initiation and progression is the WNT pathway. Breast cancer has been associated with activation of the WNT signaling pathway, although the underlying molecular mechanisms are still unclear. Here, we found the WNT receptor ROR2 to be highly expressed in aggressive breast tumors and associated with worse metastasis-free survival. In this study we addressed this question and demonstrated for the first time that WNT11 is a novel ligand for ROR2 in humans. WNT11 binds to the CRD of ROR2 and mediates WNT/PCP signaling via the RHO/ROCK pathway that confers an aggressive phenotype to breast cancer cells. ROR2 and WNT11 are both highly expressed in human brain metastases and linked with short patient survival.
2022-02-21 | GSE161865 | GEO
Project description:Breast cancer has been associated with activation of the WNT signaling pathway, although the underlying molecular mechanisms are still unclear. In order to understand the molecular basis of these observations, we overexpressed ROR2 in human breast cancer cell lines and characterized them by RNA-Sequencing. High levels of ROR2 were associated with defects in cell morphology and cell-cell-contacts leading to increased tumor invasiveness. Using gene expression analysis we demonstrated an upregulation of several non-canonical WNT ligands in ROR2-overexpressing breast cancer cells, in particular WNT11. Knockdown of WNT11 reversed the pro-invasive phenotype and the cellular changes in ROR2-overexpressing cells. Taken together, our studies revealed a novel auto-stimulatory loop in which ROR2 triggers the expression of its own ligands, e.g. WNT11, resulting in enhanced tumor invasion associated with breast cancer metastasis.
2022-02-21 | GSE161864 | GEO
Project description:WNT11/ROR2 signaling is associated with tumor invasion and poor survival in breast cancer
| PRJNA679736 | ENA
Project description:WNT11/ROR2 signaling is associated with tumor invasion and poor survival in breast cancer [patients]
| PRJNA679738 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-02-22 | GSE161866 | GEO
Project description:Estrogen receptor-{alpha} (ER{alpha}) and its ligand estradiol play critical roles in breast cancer growth and are important therapeutic targets for this disease. Using chromatin immunoprecipitation (ChIP)-on-chip, ligand-bound ER{alpha} was recently found to function as a master transcriptional regulator via binding to many cis-acting sites genome-wide. Here, we used an alternative technology (ChIP cloning) and identified 94 ER{alpha} target loci in breast cancer cells. The ER{alpha}-binding sites contained both classic estrogen response elements and nonclassic binding sequences, showed specific transcriptional activity in reporter gene assay, and interacted with the key transcriptional regulators, including RNA polymerase II and nuclear receptor coactivator-3. The great majority of the binding sites were located in either introns or far distant to coding regions of genes. Forty-three percent of the genes that lie within 50 kb to an ER{alpha}-binding site were regulated by estradiol. Most of these genes are novel estradiol targets encoding receptors, signaling messengers, and ion binders/transporters. mRNA profiling in estradiol-treated breast cancer cell lines and tissues revealed that these genes are highly ER{alpha} responsive both in vitro and in vivo. Among estradiol-induced genes, Wnt11 was found to increase cell survival by significantly reducing apoptosis in breast cancer cells. Taken together, we showed novel genomic binding sites of ER{alpha} that regulate a novel set of genes in response to estradiol in breast cancer. Our findings suggest that at least a subset of these genes, including Wnt11, may play important in vivo and in vitro biological roles in breast cancer. Keywords: time course
2008-05-20 | GSE11506 | GEO
Project description:Estrogen receptor-{alpha} (ER{alpha}) and its ligand estradiol play critical roles in breast cancer growth and are important therapeutic targets for this disease. Using chromatin immunoprecipitation (ChIP)-on-chip, ligand-bound ER{alpha} was recently found to function as a master transcriptional regulator via binding to many cis-acting sites genome-wide. Here, we used an alternative technology (ChIP cloning) and identified 94 ER{alpha} target loci in breast cancer cells. The ER{alpha}-binding sites contained both classic estrogen response elements and nonclassic binding sequences, showed specific transcriptional activity in reporter gene assay, and interacted with the key transcriptional regulators, including RNA polymerase II and nuclear receptor coactivator-3. The great majority of the binding sites were located in either introns or far distant to coding regions of genes. Forty-three percent of the genes that lie within 50 kb to an ER{alpha}-binding site were regulated by estradiol. Most of these genes are novel estradiol targets encoding receptors, signaling messengers, and ion binders/transporters. mRNA profiling in estradiol-treated breast cancer cell lines and tissues revealed that these genes are highly ER{alpha} responsive both in vitro and in vivo. Among estradiol-induced genes, Wnt11 was found to increase cell survival by significantly reducing apoptosis in breast cancer cells. Taken together, we showed novel genomic binding sites of ER{alpha} that regulate a novel set of genes in response to estradiol in breast cancer. Our findings suggest that at least a subset of these genes, including Wnt11, may play important in vivo and in vitro biological roles in breast cancer. Experiment Overall Design: This Series currently contains the gene expression data accompanying Zhihong Lin et al. Cancer Research 67,5017-5024(2007). MCF7 cells were treated with vehicle or E2 at a concentration of 10E-9 mol/L for 3 and 6 h. All experiments were performed in triplicate.
2008-06-20 | E-GEOD-11506 | biostudies-arrayexpress
Project description:The receptor-tyrosine kinase Ror2 acts as an alternative receptor or co-receptor for Wnt5a and mediates Wnt5a-induced convergent extension movements during embryogenesis in mice and Xenopus as well as the polarity and migration of several cell types during development. However, little is known about whether Ror2 function is conserved in other vertebrates or is involved in other non-canonical Wnt ligands in vivo. In this study we demonstrated that overexpression of dominant-negative ror2 (ror2-TM) mRNA in zebrafish embryos resulted in convergence and extension defects and incompletely separated eyes, which is consistent with observations from slb/wnt11 mutants or wnt11 knockdown morphants. Moreover, the co-injection of ror2-TM mRNA and a wnt11 morpholino or the coexpression of ror2 and wnt11 in zebrafish embryos synergetically induced more severe convergence and extension defects. Transplantation studies further demonstrated that the Ror2 receptor responded to the Wnt11 ligand and regulated cell migration and cell morphology during gastrulation. DnRor2 inhibited the action of Wnt11, which was revealed by a decreased percentage of Wnt11-induced convergence and extension defects. Ror2 physically interacts with Wnt11. Theintracellular Tyr-647andSer-863 sites ofRor2are essential for mediating the action of Wnt11. Dishevelled and RhoA act downstream of Wnt11-Ror2 to regulate convergence and extension movements. Overall, our data suggest an important role of Ror2 in mediating Wnt11 signaling and in regulating convergence and extension movements in zebrafish.
| S-EPMC4110278 | biostudies-literature
Project description:The goal of this study was to identify changes in gene expression within nephron progenitors and the whole embryonic kidney between Wnt11 mutants and wild type animals. Wnt11 mutant kidneys have disorganized nephron progenitor niches. Ultimately, nephron endowment is reduced by 50% in Wnt11 mutants. Gene expression changes are minimal between mutant and wild type samples, suggesting Wnt11 may act through non-canonical, non-transcritional mechanisms to regulate kidney development.
2018-10-31 | GSE118334 | GEO
Project description:Cellular heterogeneity in breast cancer encompasses many features, yet an understanding of the coexistence and regulation of various tumor cell subpopulations remains a significant challenge in cancer biology. In the current study, we approached tumor cell heterogeneity from the perspective of Wnt pathway biology to address how different modes of Wnt signaling shape the behaviors of diverse cell populations within a heterogeneous tumor landscape. Using a syngeneic TP53 null mouse model of breast cancer, we identified distinctions in the topology of canonical Wnt b-catenin dependent signaling activity and noncanonical b-catenin independent Ror2-mediated Wnt signaling across subtypes and within tumor cell subpopulations in vivo. We further discovered an antagonistic role for Ror2 in regulating canonical Wnt/b-catenin activity in vivo, where lentiviral shRNA depletion of Ror2 expression augmented canonical Wnt/b-catenin signaling activity across multiple basal-like models. Depletion of Ror2 expression yielded distinct phenotypic outcomes and divergent alterations in gene expression programs among different tumors, despite all sharing basal-like features. Notably, we uncovered cell state plasticity and adhesion dynamics regulated by Ror2, where Ras Homology Family Member A (RhoA) and Rho-Associated Coiled-Coil Kinase 1 (ROCK1) activity downstream of Dishevelled-2 (Dvl2) were implicated. Collectively, these studies illustrate the integration and collaboration of Wnt pathways in basal-like breast cancer, where Ror2 provides a spatiotemporal function to regulate the balance of Wnt signaling and cellular heterogeneity during tumor progression.
2017-01-23 | GSE93815 | GEO