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LRP6; low density lipoprotein receptor-related protein 6 (12p13.2)

Gene Summary

Gene:LRP6; low density lipoprotein receptor-related protein 6
Aliases: ADCAD2
Location:12p13.2
Summary:This gene encodes a member of the low density lipoprotein (LDL) receptor gene family. LDL receptors are transmembrane cell surface proteins involved in receptor-mediated endocytosis of lipoprotein and protein ligands. The protein encoded by this gene functions as a receptor or, with Frizzled, a co-receptor for Wnt and thereby transmits the canonical Wnt/beta-catenin signaling cascade. Through its interaction with the Wnt/beta-catenin signaling cascade this gene plays a role in the regulation of cell differentiation, proliferation, and migration and the development of many cancer types. This protein undergoes gamma-secretase dependent RIP- (regulated intramembrane proteolysis) processing but the precise locations of the cleavage sites have not been determined.[provided by RefSeq, Dec 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:low-density lipoprotein receptor-related protein 6
HPRD
Source:NCBI
Updated:12 December, 2014

Gene
Ontology:

What does this gene/protein do?
Show (97)

Pathways:

What pathways are this gene/protein implicaed in?
- Wnt signaling pathway KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 12 December 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Hepatocellular Carcinoma
  • Cultured Cells
  • Receptors, LDL
  • Cancer Gene Expression Regulation
  • Cell Proliferation
  • Wnt Proteins
  • Cell Movement
  • Signal Transduction
  • RTPCR
  • HEK293 Cells
  • LDL-Receptor Related Proteins
  • Chromosome 12
  • Gene Expression Profiling
  • Young Adult
  • Neoplasm Proteins
  • TCF Transcription Factors
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Transfection
  • Low Density Lipoprotein Receptor-Related Protein-5
  • Neoplasm Invasiveness
  • Down-Regulation
  • Wnt Signaling Pathway
  • Intercellular Signaling Peptides and Proteins
  • Phosphorylation
  • Cell Line
  • Liver Cancer
  • Immunohistochemistry
  • DNA-Binding Proteins
  • Mutation
  • Cell Survival
  • siRNA
  • Neoplastic Cell Transformation
  • Transcription Factors
  • beta Catenin
  • Wnt1 Protein
  • Translocation
  • Apoptosis
  • Tumor Suppressor Proteins
  • Breast Cancer
Tag cloud generated 12 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (2)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Breast CancerLRP6 and Breast Cancer View Publications5
Liver CancerLRP6 and Liver Cancer View Publications4

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Latest Publications: LRP6 (cancer-related)

Arend RC, Londoño-Joshi AI, Samant RS, et al.
Inhibition of Wnt/β-catenin pathway by niclosamide: a therapeutic target for ovarian cancer.
Gynecol Oncol. 2014; 134(1):112-20 [PubMed] Related Publications
Objective. The Wnt/β-catenin pathway is known to regulate cellular proliferation and plays a role in chemoresistance. Niclosamide, an FDA approved salicyclamide derivative used for the treatment of tapeworm infections, targets the Wnt/β-catenin pathway. Therefore, the objective of this study was to investigate niclosamide as a potential therapeutic agent for ovarian cancer. Methods. Tumor cells isolated from 34 patients' ascites with primary ovarian cancer were treated with niclosamide (0.1 to 5 μM) ± carboplatin (5 to 150 μM). Cell viability was assessed using the ATP-lite assay. LRP6, Axin 2, Cyclin D1, survivin and cytosolic free β-catenin levels were determined using Western blot analysis. Tumorspheres were treated, and Wnt transcriptional activity was measured by the TOPflash reporter assay. ALDH and CD133 were analyzed by Flow cytometry and IHC. ALDH1A1 and LRP6 were analyzed by IHC in solid tumor and in ascites before and after treatment with niclosamide. Results. Combination treatment produced increased cytotoxicity compared to single agent treatment in 32/34 patient samples. Western blot analysis showed a decrease in Wnt/β-catenin pathway proteins and the expression of target genes. A significant reduction of Wnt/β-catenin signaling was confirmed by TOPflash assay. There was increased staining of ALDH1A1 and LRP6 in ascites compared to solid tumor which decreased after treatment. Conclusion. This study demonstrates that niclosamide is a potent Wnt/β-catenin inhibitor. Targeting the Wnt/β-catenin pathway led to decreased cellular proliferation and increased cell death. These findings warrant further research of this drug and other niclosamide analogs as a treatment option for ovarian cancer.

Related: Carboplatin Ovarian Cancer


Zhang Y, Zheng D, Xiong Y, et al.
miR-202 suppresses cell proliferation in human hepatocellular carcinoma by downregulating LRP6 post-transcriptionally.
FEBS Lett. 2014; 588(10):1913-20 [PubMed] Related Publications
MicroRNAs have emerged as important regulators of carcinogenesis. In the current study, we observed that microRNA-202 (miR-202) is downregulated in hepatocellular carcinoma (HCC) cells and tissues, indicating a significant correlation between miR-202 expression and HCC progression. Overexpression of miR-202 in HCC cells suppressed cell proliferation and tumorigenicity, while downregulation of miR-202 enhanced the cells' proliferative capacity. Furthermore, we identified low-density lipoprotein receptor-related protein 6 (LRP6) as a direct target of miR-202. miR-202 suppresses the expression of LRP6 by binding to the 3'-untranslated region (UTR) of its mRNA. Finally, we found that silencing the expression of LRP6 is the essential biological function of miR-202 during HCC cell proliferation. Collectively, our findings reveal that miR-202 is a potential tumor suppressive miRNA that participates in carcinogenesis of human HCC by suppressing LRP6 expression.

Related: Liver Cancer


Ibrahim SA, Hassan H, Vilardo L, et al.
Syndecan-1 (CD138) modulates triple-negative breast cancer stem cell properties via regulation of LRP-6 and IL-6-mediated STAT3 signaling.
PLoS One. 2013; 8(12):e85737 [PubMed] Free Access to Full Article Related Publications
Syndecan-1 (CD138), a heparan sulfate proteoglycan, acts as a coreceptor for growth factors and chemokines and is a molecular marker associated with epithelial-mesenchymal transition during development and carcinogenesis. Resistance of Syndecan-1-deficient mice to experimentally-induced tumorigenesis has been linked to altered Wnt-responsive precursor cell pools, suggesting a potential role of Syndecan-1 in breast cancer cell stem function. However, the precise molecular mechanism is still elusive. Here, we decipher the functional impact of Syndecan-1 knockdown using RNA interference on the breast cancer stem cell phenotype of human triple-negative MDA-MB-231 and hormone receptor-positive MCF-7 cells in vitro employing an analytical flow cytometric approach. Successful Syndecan-1 siRNA knockdown was confirmed by flow cytometry. Side population measurement by Hoechst dye exclusion and Aldehyde dehydrogenase-1 activity revealed that Syndecan-1 knockdown in MDA-MB-231 cells significantly reduced putative cancer stem cell pools by 60% and 27%, respectively, compared to controls. In MCF-7 cells, Syndecan-1 depletion reduced the side population by 40% and Aldehyde dehydrogenase-1 by 50%, repectively. In MDA-MB-231 cells, the CD44(+)CD24(-/low) phenotype decreased significantly by 6% upon siRNA-mediated Syndecan-1 depletion. Intriguingly, IL-6, its receptor sIL-6R, and the chemokine CCL20, implicated in regulating stemness-associated pathways, were downregulated by >40% in Syndecan-1-silenced MDA-MB-231 cells, which showed a dysregulated response to IL-6-induced shifts in E-cadherin and vimentin expression. Furthermore, activation of STAT-3 and NFkB transcription factors and expression of a coreceptor for Wnt signaling, LRP-6, were reduced by >45% in Syndecan-1-depleted cells compared to controls. At the functional level, Syndecan-1 siRNA reduced the formation of spheres and cysts in MCF-7 cells grown in suspension culture. Our study demonstrates the viability of flow cytometric approaches in analyzing cancer stem cell function. As Syndecan-1 modulates the cancer stem cell phenotype via regulation of the Wnt and IL-6/STAT3 signaling pathways, it emerges as a promising novel target for therapeutic approaches.

Related: Signal Transduction


Marastoni S, Andreuzzi E, Paulitti A, et al.
EMILIN2 down-modulates the Wnt signalling pathway and suppresses breast cancer cell growth and migration.
J Pathol. 2014; 232(4):391-404 [PubMed] Related Publications
EMILIN2 is an extracellular matrix (ECM) protein that exerts contradictory effects within the tumour microenvironment: it induces apoptosis in a number of tumour cells, but it also enhances tumour neo-angiogenesis. In this study, we describe a new mechanism by which EMILIN2 attenuates tumour cell viability. Based on sequence homology with the cysteine-rich domain (CRD) of the Frizzled receptors, we hypothesized that EMILIN2 could affect Wnt signalling activation and demonstrate direct interaction with the Wnt1 ligand. This physical binding leads to decreased LRP6 phosphorylation and to the down-modulation of β-catenin, TAZ and their target genes. As a consequence, EMILIN2 negatively affects the viability, migration and tumourigenic potential of MDA-MB-231 breast cancer cells in a number of two- and three-dimensional in vitro assays. EMILIN2 does not modulate Wnt signalling downstream of the Wnt-Frizzled interaction, since it does not affect the activation of the pathway following treatment with the GSK3 inhibitors LiCl and CHIR99021. The interaction with Wnt1 and the subsequent biological effects require the presence of the EMI domain, as there is no effect with a deletion mutant lacking this domain. Moreover, in vivo experiments show that the ectopic expression of EMILIN2, as well as treatment with the recombinant protein, significantly reduce tumour growth and dissemination of cancer cells in nude mice. Accordingly, the tumour samples are characterized by a significant down-regulation of the Wnt signalling pathway. Altogether, these findings provide further evidence of the complex regulations governed by EMILIN2 in the tumour microenvironment, and they identify a key extracellular regulator of the Wnt signalling pathway.

Related: Breast Cancer CTNNB1 gene


Wang J, Wang X, Li Z, et al.
MicroRNA-183 suppresses retinoblastoma cell growth, invasion and migration by targeting LRP6.
FEBS J. 2014; 281(5):1355-65 [PubMed] Related Publications
Our study demonstrates the downregulation of microRNA-183 (miR-183) in retinoblastoma (RB) tissues and RB cell lines compared with normal retinal tissues. The ectopic expression of miR-183 in the RB cell lines Y79, SO-RB50 and WERI-RB1 suppresses cell viability, migration and invasion. Furthermore, the Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6) was identified as a new target of miR-183, and restoration of the expression of LRP6 rescues the effects induced by miR-183 in RB cells. These results indicate that miR-183 targets and downregulates LRP6 in the growth, migration and invasion of RB cells.

Related: Apoptosis Retinoblastoma


Liu J, Pan S, Hsieh MH, et al.
Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974.
Proc Natl Acad Sci U S A. 2013; 110(50):20224-9 [PubMed] Free Access to Full Article Related Publications
Wnt signaling is one of the key oncogenic pathways in multiple cancers, and targeting this pathway is an attractive therapeutic approach. However, therapeutic success has been limited because of the lack of therapeutic agents for targets in the Wnt pathway and the lack of a defined patient population that would be sensitive to a Wnt inhibitor. We developed a screen for small molecules that block Wnt secretion. This effort led to the discovery of LGK974, a potent and specific small-molecule Porcupine (PORCN) inhibitor. PORCN is a membrane-bound O-acyltransferase that is required for and dedicated to palmitoylation of Wnt ligands, a necessary step in the processing of Wnt ligand secretion. We show that LGK974 potently inhibits Wnt signaling in vitro and in vivo, including reduction of the Wnt-dependent LRP6 phosphorylation and the expression of Wnt target genes, such as AXIN2. LGK974 is potent and efficacious in multiple tumor models at well-tolerated doses in vivo, including murine and rat mechanistic breast cancer models driven by MMTV-Wnt1 and a human head and neck squamous cell carcinoma model (HN30). We also show that head and neck cancer cell lines with loss-of-function mutations in the Notch signaling pathway have a high response rate to LGK974. Together, these findings provide both a strategy and tools for targeting Wnt-driven cancers through the inhibition of PORCN.

Related: Cancer Prevention and Risk Reduction


Fang LT, Lee S, Choi H, et al.
Comprehensive genomic analyses of a metastatic colon cancer to the lung by whole exome sequencing and gene expression analysis.
Int J Oncol. 2014; 44(1):211-21 [PubMed] Related Publications
We performed whole exome sequencing and gene expression analysis on a metastatic colon cancer to the lung, along with the adjacent normal tissue of the lung. Whole exome sequencing uncovered 71 high-confidence non‑synonymous mutations. We selected 16 mutation candidates, and 13 out of 16 mutations were validated by targeted deep sequencing using the Ion Torrent PGM customized AmpliSeq panel. By integrating mutation, copy number and gene expression microarray data, we identified a JAZF1 mutation with a gain-of-copy, suggesting its oncogenic potential for the lung metastasis from colon cancer. Our pathway analyses showed that the identified mutations closely reflected characteristics of the metastatic site (lung) while mRNA gene expression patterns kept genetic information of its primary tumor (colon). The most significant gene expression network was the 'Colorectal Cancer Metastasis Signaling', containing 6 (ADCY2, ADCY9, APC, GNB5, K-ras and LRP6) out of the 71 mutated genes. Some of these mutated genes (ADCY9, ADCY2, GNB5, K-ras, HDAC6 and ARHGEF17) also belong to the 'Phospholipase C Signaling' network, which suggests that this pathway and its mutated genes may contribute to a lung metastasis from colon cancer.


Rasmussen NR, Wright TM, Brooks SA, et al.
Receptor tyrosine kinase-like orphan receptor 2 (Ror2) expression creates a poised state of Wnt signaling in renal cancer.
J Biol Chem. 2013; 288(36):26301-10 [PubMed] Free Access to Full Article Related Publications
Expression of the receptor tyrosine kinase-like orphan receptor 2 (Ror2) has been identified in an increasing array of tumor types and is known to play a role as an important mediator of Wnt signaling cascades. In this study, we aimed to clarify Ror2 interactions with the Wnt pathways within the context of renal cell carcinoma (RCC). An examination of Ror2 expression in primary human RCC tumors showed a significant correlation with several Wnt signaling genes, including the classical feedback target gene Axin2. We provide evidence that Ror2 expression results in a partially activated state for canonical Wnt signaling through an increased signaling pool of β-catenin, leading to an enhancement of downstream target genes following Wnt3a stimulation in both renal and renal carcinoma-derived cells. Additionally, inhibition of low-density lipoprotein receptor-related protein 6 (LRP6) with either siRNA or dickkopf decreased the response to Wnt3a stimulation, but no change was seen in the increased β-catenin pool associated with Ror2 expression, suggesting that LRP6 cofactor recruitment is necessary for a Wnt3a-induced signal but that it does not participate in the Ror2 effect on β-catenin signaling. These results highlight a new role for Ror2 in conveying a tonic signal to stabilize soluble β-catenin and create a poised state of enhanced responsiveness to Wnt3a exogenous signals in RCC.

Related: Kidney Cancer CTNNB1 gene


Parviainen H, Schrade A, Kiiveri S, et al.
Expression of Wnt and TGF-β pathway components and key adrenal transcription factors in adrenocortical tumors: association to carcinoma aggressiveness.
Pathol Res Pract. 2013; 209(8):503-9 [PubMed] Free Access to Full Article Related Publications
Factors controlling benign and malignant adrenocortical tumorigenesis are largely unknown, but several mouse models suggest an important role for inhibin-alpha (INHA). To show that findings in the mouse are relevant to human tumors and clinical outcome, we investigated the expression of signaling proteins and transcription factors involved in the regulation of INHA in human tumor samples⋅ Thirty-one adrenocortical tumor samples, including 13 adrenocortical carcinomas (ACCs), were categorized according to Weiss score, hormonal profile, and patient survival data and analyzed using immunohistochemistry and RT-PCR. Expression of the TGF-β signaling mediator SMAD3 varied inversely with Weiss score, so that SMAD3 expression was lowest in the most malignant tumors. By contrast, SMAD2 expression was upregulated in most malignant tumors. Wnt pathway co-receptors LRP5 and LRP6 were predominantly expressed in benign adrenocortical tumors. In ACCs, expression of transcription factors GATA-6 and SF-1 correlated with that of their target gene INHA. Moreover, the diminished expression of GATA-6 and SF-1 in ACCs correlated with poor outcome. We conclude that the factors driving INHA expression are reduced in ACCs with poor outcome, implicating a role for INHA as a tumor suppressor in humans.

Related: Adrenocortical Cancer Adrenocortical Carcinoma - Molecular Biology SMAD3 CTNNB1 gene


Chen D, Bhat-Nakshatri P, Goswami C, et al.
ANTXR1, a stem cell-enriched functional biomarker, connects collagen signaling to cancer stem-like cells and metastasis in breast cancer.
Cancer Res. 2013; 73(18):5821-33 [PubMed] Free Access to Full Article Related Publications
Cancer stem-like cells are thought to contribute to tumor recurrence. The anthrax toxin receptor 1 (ANTXR1) has been identified as a functional biomarker of normal stem cells and breast cancer stem-like cells. Primary stem cell-enriched basal cells (CD49f(+)/EpCAM(-)/Lin(-)) expressed higher levels of ANTXR1 compared with mature luminal cells. CD49f(+)/EpCAM(-), CD44(+)/EpCAM(-), CD44(+)/CD24(-), or ALDEFLUOR-positive subpopulations of breast cancer cells were enriched for ANTXR1 expression. CD44(+)/CD24(-)/ANTXR1(+) cells displayed enhanced self-renewal as measured by mammosphere assay compared with CD44(+)/CD24(-)/ANTXR1(-) cells. Activation of ANTXR1 by its natural ligand C5A, a fragment of collagen VI α3, increased stem cell self-renewal in mammosphere assays and Wnt signaling including the expression of the Wnt receptor-lipoprotein receptor-related protein 6 (LRP6), phosphorylation of GSK3α/β, and elevated expression of Wnt target genes. RNAi-mediated silencing of ANTXR1 enhanced the expression of luminal-enriched genes but diminished Wnt signaling including reduced LRP6 and ZEB1 expression, self-renewal, invasion, tumorigenicity, and metastasis. ANTXR1 silencing also reduced the expression of HSPA1A, which is overexpressed in metastatic breast cancer stem cells. Analysis of public databases revealed ANTXR1 amplification in medullary breast carcinoma and overexpression in estrogen receptor-negative breast cancers with the worst outcome. Furthermore, ANTXR1 is among the 10% most overexpressed genes in breast cancer and is coexpressed with collagen VI. Thus, ANTXR1:C5A interactions bridge a network of collagen cleavage and remodeling in the tumor microenvironment, linking it to a stemness signaling network that drives metastatic progression.

Related: Apoptosis Breast Cancer


Shen W, Zou X, Chen M, et al.
Effect of pantoprazole on human gastric adenocarcinoma SGC7901 cells through regulation of phospho‑LRP6 expression in Wnt/β-catenin signaling.
Oncol Rep. 2013; 30(2):851-5 [PubMed] Related Publications
Recent studies have found that an acidic tumor microenvironment is the key to managing cancer progression and metastasis. Our previous study found that proton pump inhibitors (PPIs) inhibit the expression of vacuolar-ATPases (V-ATPases) and reverse the transmembrane pH gradient. The present study was conducted to explore the effect of pantoprazole on gastric adenocarcinoma through the regulation of Wnt/β-catenin signaling. We used SGC7901 human gastric cancer cells as an in vitro model to study the effect of pantoprazole. The antiproliferative, pro-apoptotic and anti‑invasive effects of pantoprazole were examined. The effects of pantoprazole on the expression of the Wnt/β-catenin signaling pathway were also studied by western blotting. Our study found that pantoprazole inhibited the proliferation and induced the apoptosis of SGC7901 human gastric cancer cells. The expression of V-ATPases was decreased following treatment with pantoprazole. Further study found that pantoprazole treatment caused a decrease in phospho-LRP6, but not in LRP6. β-catenin in Wnt/β-catenin signaling and its target genes c-Myc and cyclin D1 were also decreased upon the inhibition of V-ATPases. Therefore, pantoprazole could be characterized as a V-ATPase inhibitor for treating gastric cancer by inhibiting the phosphorylation of LRP6 in Wnt/β-catenin signaling.

Related: Apoptosis Stomach Cancer Gastric Cancer


Yan X, Lyu T, Jia N, et al.
Huaier aqueous extract inhibits ovarian cancer cell motility via the AKT/GSK3β/β-catenin pathway.
PLoS One. 2013; 8(5):e63731 [PubMed] Free Access to Full Article Related Publications
Traditional Chinese medicine has gained popularity due to its ability to kill tumor cells. Recently, the apoptotic and anti-angiogenic effects of Trametes robiniophila murr (Huaier) have been investigated. The aim of this study was to investigate its effect on cell mobility and tumor growth in ovarian cancer. Cell viability and motility were measured using SRB, scratch and migration assays. Cell apoptosis was analysed by annexin V/PI staining. Using a reverse-phase protein array (RPPA) assay, we analyzed the levels of 153 proteins and/or phosphorylations in Huaier-treated and untreated cells. Huaier inhibited cell viability and induced both early and late apoptosis in SKOV3, SKOV3.ip1 and Hey cells in a time- and dose-dependent manner. Cell invasiveness and migration were also suppressed significantly. The RPPA results showed significant differences (of at least 30%; P <0.05) in the levels of 7 molecules in SKOV3 cells and 10 in SKOV3.ip1 cells between the untreated and treated cells. Most of the molecules identified play roles in cell proliferation, apoptosis or cell adhesion/invasion. Western blot analysis further validated that Huaier treatment resulted in decreased AKT phosphorylation, enhanced expression of total GSK3β, inhibition of the phosphorylation of GSK3β on S9, reduction of both cytoplasmic β-catenin expression and nuclear β-catenin translocation, and transcriptional repression of several Wnt/β-catenin target genes (DIXDC1, LRP6, WNT5A, and cyclin D1). After knocking down GSK3β, β-catenin expression could not be inhibited by Huaier. Finally, Huaier inhibited the growth of ovarian tumor xenografts in vivo. These studies indicate that Huaier inhibits tumor cell mobility in ovarian cancer via the AKT/GSK3β/β-catenin signaling pathway.

Related: Apoptosis Ovarian Cancer AKT1 Signal Transduction CTNNB1 gene


Zhang J, Yang Z, Li P, et al.
Kallistatin antagonizes Wnt/β-catenin signaling and cancer cell motility via binding to low-density lipoprotein receptor-related protein 6.
Mol Cell Biochem. 2013; 379(1-2):295-301 [PubMed] Free Access to Full Article Related Publications
Kallistatin, a plasma protein, exerts pleiotropic effects in inhibiting angiogenesis, inflammation and tumor growth. Canonical Wnt signaling is the primary pathway for oncogenesis in the mammary gland. In this study, we demonstrate that kallistatin bound to the Wnt coreceptor low-density lipoprotein receptor-related protein 6 (LRP6), thus, blocking Wnt/β-catenin signaling and Wnt-mediated growth and migration in MDA-MB-231 breast cancer cells. Kallistatin inhibited Wnt3a-induced proliferation, migration, and invasion of cultured breast cancer cells. Moreover, kallistatin was bound to LRP6 in breast cancer cells, as identified by immunoprecipitation followed by western blot. Kallistatin suppressed Wnt3a-mediated phosphorylation of LRP6 and glycogen synthase kinase-3β, and the elevation of cytosolic β-catenin levels. Furthermore, kallistatin antagonized Wnt3a-induced expression of c-Myc, cyclin D1, and vascular endothelial growth factor. These findings indicate a novel role of kallistatin in preventing breast tumor growth and mobility by direct interaction with LRP6, leading to blockade of the canonical Wnt signaling pathway.

Related: Breast Cancer VEGFA BCL1 Gene (CCND1)


Grossmann AH, Yoo JH, Clancy J, et al.
The small GTPase ARF6 stimulates β-catenin transcriptional activity during WNT5A-mediated melanoma invasion and metastasis.
Sci Signal. 2013; 6(265):ra14 [PubMed] Free Access to Full Article Related Publications
β-Catenin has a dual function in cells: fortifying cadherin-based adhesion at the plasma membrane and activating transcription in the nucleus. We found that in melanoma cells, WNT5A stimulated the disruption of N-cadherin and β-catenin complexes by activating the guanosine triphosphatase adenosine diphosphate ribosylation factor 6 (ARF6). Binding of WNT5A to the Frizzled 4-LRP6 (low-density lipoprotein receptor-related protein 6) receptor complex activated ARF6, which liberated β-catenin from N-cadherin, thus increasing the pool of free β-catenin, enhancing β-catenin-mediated transcription, and stimulating invasion. In contrast to WNT5A, the guidance cue SLIT2 and its receptor ROBO1 inhibited ARF6 activation and, accordingly, stabilized the interaction of N-cadherin with β-catenin and reduced transcription and invasion. Thus, ARF6 integrated competing signals in melanoma cells, thereby enabling plasticity in the response to external cues. Moreover, small-molecule inhibition of ARF6 stabilized adherens junctions, blocked β-catenin signaling and invasiveness of melanoma cells in culture, and reduced spontaneous pulmonary metastasis in mice, suggesting that targeting ARF6 may provide a means of inhibiting WNT/β-catenin signaling in cancer.

Related: Melanoma Signal Transduction CTNNB1 gene


Huang X, McGann JC, Liu BY, et al.
Phosphorylation of Dishevelled by protein kinase RIPK4 regulates Wnt signaling.
Science. 2013; 339(6126):1441-5 [PubMed] Free Access to Full Article Related Publications
Receptor-interacting protein kinase 4 (RIPK4) is required for epidermal differentiation and is mutated in Bartsocas-Papas syndrome. RIPK4 binds to protein kinase C, but its signaling mechanisms are largely unknown. Ectopic RIPK4, but not catalytically inactive or Bartsocas-Papas RIPK4 mutants, induced accumulation of cytosolic β-catenin and a transcriptional program similar to that caused by Wnt3a. In Xenopus embryos, Ripk4 synergized with coexpressed Xwnt8, whereas Ripk4 morpholinos or catalytic inactive Ripk4 antagonized Wnt signaling. RIPK4 interacted constitutively with the adaptor protein DVL2 and, after Wnt3a stimulation, with the co-receptor LRP6. Phosphorylation of DVL2 by RIPK4 favored canonical Wnt signaling. Wnt-dependent growth of xenografted human tumor cells was suppressed by RIPK4 knockdown, suggesting that RIPK4 overexpression may contribute to the growth of certain tumor types.

Related: Cancer Prevention and Risk Reduction Ovarian Cancer CTNNB1 gene


Wang H, He L, Ma F, et al.
SOX9 regulates low density lipoprotein receptor-related protein 6 (LRP6) and T-cell factor 4 (TCF4) expression and Wnt/β-catenin activation in breast cancer.
J Biol Chem. 2013; 288(9):6478-87 [PubMed] Free Access to Full Article Related Publications
Gene expression profiling has identified breast cancer (BCa) subtypes, including an aggressive basal-like (BL) subtype. The molecular signals underlying the behavior observed in BL-BCa group are largely unknown, although recent results indicate a prevalent increase in Wnt/β-catenin activity. Our immunohistochemistry study confirmed that SOX9, one of the BL-BCa signature genes, was expressed by most BL-BCa, and its expression correlated with indicators of poor prognosis. Importantly, BCa gene expression profiling strongly associated SOX9 with the expression of Wnt/β-catenin pathway components, LRP6 and TCF4. In cancer cell lines, SOX9 silencing reduced cell proliferation and invasion, LRP6 and TCF4 transcription, and decreased Wnt/β-catenin activation. SOX9 expression was also increased by Wnt, indicating that SOX9 is at the center of a positive feedback loop that enhances Wnt/β-catenin signaling. Consistently, SOX9 overexpression in BCa cell lines and transgenic SOX9 expression in breast epithelium caused increased LRP6 and TCF4 expression and Wnt/β-catenin activation. These results identify SOX9-mediated Wnt/β-catenin activation as one of the molecular mechanisms underlying aberrant Wnt/β-catenin activity in BCa, especially in the BL-BCa subgroup.

Related: Breast Cancer CTNNB1 gene


Tahir SA, Yang G, Goltsov A, et al.
Caveolin-1-LRP6 signaling module stimulates aerobic glycolysis in prostate cancer.
Cancer Res. 2013; 73(6):1900-11 [PubMed] Free Access to Full Article Related Publications
Caveolin 1 (Cav-1) is a plasma membrane-associated protein with the capacity to modulate signaling activities in a context-dependent fashion. Interactions between Cav-1 and low-density lipoprotein receptor-related protein 6 (LRP6) were reported to be important for the regulation of Wnt-β-catenin (β-cat) signaling. Cav-1 also interacts with insulin and IGF-I receptors (IGF-IR/IR) and can stimulate IR kinase activities. We found positive correlation between Cav-1 and LRP6 expression in both human primary prostate cancer and metastasis tissues and in PC-3 cells. Cav-1 stimulation of Wnt-β-cat signaling and c-Myc levels was positively associated with LRP6 expression in LNCaP, PC-3, and DU145 prostate cancer cells. Importantly, LRP6 and, to a lesser extent, Cav-1 were found to stimulate aerobic glycolysis. These activities were positively associated with the expression of HK2 and Glut3 and shown to be dependent on Akt signaling by both gene knockdown and chemical inhibition methods. We further showed that Cav-1 and LRP6 exert their effects on Akt and glycolytic activities by stimulating IGF-IR/IR signaling. Overall, our results show that Cav-1 interacts with LRP6 to generate an integrated signaling module that leads to the activation of IGF-IR/IR and results in stimulation of Akt-mTORC1 signaling and aerobic glycolysis in prostate cancer.

Related: Prostate Cancer Signal Transduction


Cho SW, Lee EJ, Kim H, et al.
Dickkopf-1 inhibits thyroid cancer cell survival and migration through regulation of β-catenin/E-cadherin signaling.
Mol Cell Endocrinol. 2013; 366(1):90-8 [PubMed] Related Publications
Wnt/β-catenin signaling plays a role in tumorigenesis of human papillary thyroid cancer (PTC). Dickkopf-1 (Dkk-1) is an inhibitor of Wnt/β-catenin signaling. We investigated the therapeutic potential of Dkk-1 in human PTC cell lines, SNU-790, B-CPAP, and BHP10-3. Dkk-1 reversed the aberrant expression of β-catenin from nucleus to membrane and inhibited basal levels of TCF/LEF-dependent transcriptional activities. Furthermore, Dkk-1 inhibited cell viability in a dose-dependent manner and adenoviral transduction of constitutively active β-catenin blocked these effects, thus suggesting that the Dkk-1 anti-tumoral effect is mediated by Wnt/β-catenin signaling. Bromodeoxyuridine assay showed minimal effects of Dkk-1 on cell proliferation. Flow cytometric analysis with Annexin V staining showed marked induction of cell apoptosis by Dkk-1 treatment. Dkk-1 also restored the loss of membranous E-cadherin expression with consequent inhibition of cell migration and invasion. In conclusion, Dkk-1 inhibited the survival and migration of human PTC cells by regulating Wnt/β-catenin signaling and E-cadherin expression.

Related: Apoptosis Signal Transduction Thyroid Cancer CTNNB1 gene CDH1


Al-Shehhi H, Konn ZJ, Schwab CJ, et al.
Abnormalities of the der(12)t(12;21) in ETV6-RUNX1 acute lymphoblastic leukemia.
Genes Chromosomes Cancer. 2013; 52(2):202-13 [PubMed] Related Publications
ETV6-RUNX1 fusion [t(12;21)(p13;q22)] occurs in 25% of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and is associated with a favorable outcome. Additional abnormalities involving der(21)t(12;21) and nonrearranged chromosome 12 are well characterized but aberrations involving the der(12)t(12;21) have rarely been described. Herein, we describe two novel abnormalities affecting the der(12)t(12;21): a deletion (20/247, 8%) and duplication (10/247, 4%). All 30 patients were under 10 years of age, had a median white blood count of 12.4 × 10(9)/L and 19.2 × 10(9)/L, respectively, with a good outcome. Deletions of der(12)t(12;21) on both sides of the breakpoint were confirmed and mapped: centromeric (12p11.21-12p13.2) and telomeric (21q22.12-21q22.3). The size of these deletions extended from 0.4-13.4 to 0.8-2.5 Mb, respectively. The centromeric deletion encompassed the following genes: LRP6, BCL2L14, DUSP16, CREBL2, and CDKN1B. We postulate that this deletion occurs at the same time as the translocation because it was present in all ETV6-RUNX1-positive cells. A second abnormality representing duplication of the reciprocal RUNX1-ETV6 fusion gene was a secondary event, which we hypothesize arose through mitotic recombination errors. This led to the formation of the following chromosome: der(12)(21qter→21q22.12::12p13.2-12p12.3::12p12.3→12qter). Both abnormalities affect the reciprocal RUNX1-ETV6 fusion product which could either eliminate or amplify its expression and thus contribute to leukemogenesis. However, other consequences such as haploinsufficiency of tumor suppressor genes and amplification of oncogenes could also be driving forces behind these aberrations. In conclusion, this study has defined novel abnormalities in ETV6-RUNX1 BCP-ALL, which implicate new genes involved in leukemogenesis.

Related: Chromosome 12 Chromosome 21 CDKN1B FISH Acute Lymphocytic Leukemia (ALL) Childhood Acute lymphoblastic leukaemia (ALL) ALL - Molecular Biology


Gong X, Carmon KS, Lin Q, et al.
LGR6 is a high affinity receptor of R-spondins and potentially functions as a tumor suppressor.
PLoS One. 2012; 7(5):e37137 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: LGR6 (leucine-rich repeat containing, G protein-coupled receptor 6) is a member of the rhodopsin-like seven transmembrane domain receptor superfamily with the highest homology to LGR4 and LGR5. LGR6 was found as one of the novel genes mutated in colon cancer through total exon sequencing and its promoter region is hypermethylated in 20-50% of colon cancer cases. In the skin, LGR6 marks a population of stem cells that can give rise to all cell lineages. Recently, we and others demonstrated that LGR4 and LGR5 function as receptors of R-spondins to potentiate Wnt/β-catenin signaling. However, the binding affinity and functional response of LGR6 to R-spondins, and the activity of colon cancer mutants of LGR6 have not been determined.
PRINCIPAL FINDINGS: We found that LGR6 also binds and responds to R-spondins 1-3 with high affinity to enhance Wnt/β-catenin signaling through increased LRP6 phosphorylation. Similar to LGR4 and LGR5, LGR6 is not coupled to heterotrimeric G proteins or to β-arrestin following R-spondin stimulation. Functional and expression analysis of three somatic mutations identified in colon cancer samples indicates that one mutant fails to bind and respond to R-spondin (loss-of-function), but the other two have no significant effect on receptor function. Overexpression of wild-type LGR6 in HeLa cells leads to increased cell migration following co-treatment with R-spondin1 and Wnt3a when compared to vector control cells or cells overexpressing the loss-of-function mutant.
CONCLUSIONS: LGR6 is a high affinity receptor for R-spondins 1-3 and potentially functions as a tumor suppressor despite its positive effect on Wnt/β-catenin signaling.

Related: Signal Transduction CTNNB1 gene


Lee JS, Hur MW, Lee SK, et al.
A novel sLRP6E1E2 inhibits canonical Wnt signaling, epithelial-to-mesenchymal transition, and induces mitochondria-dependent apoptosis in lung cancer.
PLoS One. 2012; 7(5):e36520 [PubMed] Free Access to Full Article Related Publications
Aberrant activation of the Wnt pathway contributes to human cancer progression. Antagonists that interfere with Wnt ligand/receptor interactions can be useful in cancer treatments. In this study, we evaluated the therapeutic potential of a soluble Wnt receptor decoy in cancer gene therapy. We designed a Wnt antagonist sLRP6E1E2, and generated a replication-incompetent adenovirus (Ad), dE1-k35/sLRP6E1E2, and a replication-competent oncolytic Ad, RdB-k35/sLRP6E1E2, both expressing sLRP6E1E2. sLRP6E1E2 prevented Wnt-mediated stabilization of cytoplasmic β-catenin, decreased Wnt/β-catenin signaling and cell proliferation via the mitogen-activated protein kinase, and phosphatidylinositol 3-kinase pathways. sLRP6E1E2 induced apoptosis, cytochrome c release, and increased cleavage of PARP and caspase-3. sLRP6E1E2 suppressed growth of the human lung tumor xenograft, and reduced motility and invasion of cancer cells. In addition, sLRP6E1E2 upregulated expression of epithelial marker genes, while sLRP6E1E2 downregulated mesenchymal marker genes. Taken together, sLRP6E1E2, by inhibiting interaction between Wnt and its receptor, suppressed Wnt-induced cell proliferation and epithelial-to-mesenchymal transition.

Related: Apoptosis Non-Small Cell Lung Cancer Lung Cancer Mitochondrial Mutations in Cancer CTNNB1 gene


Tung EK, Wong BY, Yau TO, Ng IO
Upregulation of the Wnt co-receptor LRP6 promotes hepatocarcinogenesis and enhances cell invasion.
PLoS One. 2012; 7(5):e36565 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Activation of the Wnt/β-catenin signaling pathway plays a crucial role in hepatocellular carcinoma (HCC). Low-density lipoprotein (LDL) receptor-related protein-6 (LRP6) is one of the co-receptors of the Wnt/β-catenin pathway and forms a signaling complex with Wnt ligand and Frizzled receptor to activate downstream signaling. However, the role of LRP6 in hepatocarcinogenesis is unclear. In this study, we examined its expression and roles in human HCC.
METHODOLOGY/PRINCIPAL FINDINGS: Using real-time quantitative RT-PCR, we found that LRP6 was frequently (45%) overexpressed in human HCCs (P = 0.003). In vitro studies showed that ectopic expression of LRP6 increased the protein level of β-catenin. Moreover, overexpression of the full-length and constitutively active LRP6, respectively, activated the WNT/β-catenin signaling pathway, as shown by the TCF/β-catenin reporter assay. With regard to the effects of LRP6 overexpression in HCC cells, stable overexpression of the constitutively active LRP6 in BEL-7402 HCC cells enhanced cell proliferation, cell migration, and invasion in vitro as well as tumorigenicity in nude mice.
CONCLUSIONS/SIGNIFICANCE: Our findings indicate that overexpression of LRP6 contributes to the hyperactivation of the Wnt/β-catenin signaling pathway in human HCCs and suggest it may play a role in hepatocarcinogenesis.

Related: Liver Cancer


Cha YH, Kim NH, Park C, et al.
MiRNA-34 intrinsically links p53 tumor suppressor and Wnt signaling.
Cell Cycle. 2012; 11(7):1273-81 [PubMed] Related Publications
Though tumor suppressor p53 and the canonical Wnt cascade have been extensively studied for the last 30 years, due to their important physiological roles, the two signaling pathways have been largely considered independent. Recently, the miR-34 family was found to directly link p53 and Wnt, revealing the tight connection between loss of tumor suppressor function and activation of oncogenic signaling. These observations demonstrate that miR-34, known to be directly downstream of p53, targets a set of highly conserved sites in the UTR of Wnt and EMT genes, specifically WNT1, WNT3, LRP6, AXIN2, β-catenin, LEF1 and Snail, resulting in suppression of TCF/LEF transcriptional activity and the EMT program. The loss of p53 function increases Wnt activities and promotes the Snail-dependent EMT program at multiple levels in a miR-34/UTR-specific manner. The TCF/LEF transcriptional signature was closely associated with functionality of p53 and miR-34 in clinical samples, suggesting the pervasive impact of miR-34 loss on the oncogenic pathway in human cancer. Here, we review recent findings on ceRNA in light of novel data to elucidate the physiological relevance of the p53-miR-34-Wnt network, which encompasses sets of genes and directions of signaling. As loss of wt-p53 or hyperactivation of Wnt is critical in maintaining cancer stem cell properties and in establishing the metastatic program, these observations indicate a mechanism of miR-mediated quasi-sufficiency which connects tumor suppressor and oncogenic signaling pathways, supporting a continuum model of human cancer.

Related: Cancer Prevention and Risk Reduction TP53


Liu W, Xing F, Iiizumi-Gairani M, et al.
N-myc downstream regulated gene 1 modulates Wnt-β-catenin signalling and pleiotropically suppresses metastasis.
EMBO Mol Med. 2012; 4(2):93-108 [PubMed] Free Access to Full Article Related Publications
Wnt signalling has pivotal roles in tumour progression and metastasis; however, the exact molecular mechanism of Wnt signalling in the metastatic process is as yet poorly defined. Here we demonstrate that the tumour metastasis suppressor gene, NDRG1, interacts with the Wnt receptor, LRP6, followed by blocking of the Wnt signalling, and therefore, orchestrates a cellular network that impairs the metastatic progression of tumour cells. Importantly, restoring NDRG1 expression by a small molecule compound significantly suppressed the capability of otherwise highly metastatic tumour cells to thrive in circulation and distant organs in animal models. In addition, our analysis of clinical cohorts data indicate that Wnt+/NDRG-/LRP+ signature has a strong predictable value for recurrence-free survival of cancer patients. Collectively, we have identified NDRG1 as a novel negative master regulator of Wnt signalling during the metastatic progression, which opens an opportunity to define a potential therapeutic target for metastatic disease.

Related: Signal Transduction CTNNB1 gene NDRG1 gene


Lu D, Choi MY, Yu J, et al.
Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells.
Proc Natl Acad Sci U S A. 2011; 108(32):13253-7 [PubMed] Free Access to Full Article Related Publications
Salinomycin, an antibiotic potassium ionophore, has been reported recently to act as a selective breast cancer stem cell inhibitor, but the biochemical basis for its anticancer effects is not clear. The Wnt/β-catenin signal transduction pathway plays a central role in stem cell development, and its aberrant activation can cause cancer. In this study, we identified salinomycin as a potent inhibitor of the Wnt signaling cascade. In Wnt-transfected HEK293 cells, salinomycin blocked the phosphorylation of the Wnt coreceptor lipoprotein receptor related protein 6 (LRP6) and induced its degradation. Nigericin, another potassium ionophore with activity against cancer stem cells, exerted similar effects. In otherwise unmanipulated chronic lymphocytic leukemia cells with constitutive Wnt activation nanomolar concentrations of salinomycin down-regulated the expression of Wnt target genes such as LEF1, cyclin D1, and fibronectin, depressed LRP6 levels, and limited cell survival. Normal human peripheral blood lymphocytes resisted salinomycin toxicity. These results indicate that ionic changes induced by salinomycin and related drugs inhibit proximal Wnt signaling by interfering with LPR6 phosphorylation, and thus impair the survival of cells that depend on Wnt signaling at the plasma membrane.

Related: Apoptosis Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology Signal Transduction CTNNB1 gene


Shen W, Zou X, Chen M, et al.
Effects of diphyllin as a novel V-ATPase inhibitor on gastric adenocarcinoma.
Eur J Pharmacol. 2011; 667(1-3):330-8 [PubMed] Related Publications
The natural compound diphyllin, a cytostatic lignan isolated from Cleistanthus collinus, can dramatically inhibit the proliferation and induce the apoptosis of human gastric cancer cells, SGC7901. Our study found that diphyllin can inhibit the expression of V-ATPases in a dose-dependent manner, decrease the internal pH (pHi) and reverse the transmembrane pH gradient in SGC7901 cells. Changes of the pH gradient were positively correlated with diphyllin concentration. Further study found that diphyllin treatment caused a decrease in phospho-LRP6, but not in LRP6. β-catenin in Wnt/β-catenin signaling and its target genes, c-myc and cyclin-D1, were also decreased with the inhibition of V-ATPases. Therefore, diphyllin could be characterized as a new V-ATPase inhibitor in treating gastric cancer and inhibiting the phosphorylation of LRP6 in Wnt/β-catenin signaling.

Related: Apoptosis Stomach Cancer Gastric Cancer


von Marschall Z, Fisher LW
Secreted Frizzled-related protein-2 (sFRP2) augments canonical Wnt3a-induced signaling.
Biochem Biophys Res Commun. 2010; 400(3):299-304 [PubMed] Free Access to Full Article Related Publications
Secreted Frizzled-related proteins (sFRP) are involved in embryonic development as well as pathological conditions including bone and myocardial disorders and cancer. Because of their sequence homology with the Wnt-binding domain of Frizzled, they have generally been considered antagonists of canonical Wnt signaling. However, additional activities of various sFRPs including both synergism and mimicry of Wnt signaling as well as functions other than modulation of Wnt signaling have been reported. Using human embryonic kidney cells (HEK293A), we found that sFRP2 enhanced Wnt3a-dependent phosphorylation of LRP6 as well as both cytosolic β-catenin levels and its nuclear translocation. While addition of recombinant sFRP2 had no activity by itself, Top/Fop luciferase reporter assays showed a dose-dependent increase of Wnt3a-mediated transcriptional activity. sFRP2 enhancement of Wnt3a signaling was abolished by treatment with the Wnt antagonist, Dickkopf-1 (DKK1). Wnt-signaling pathway qPCR arrays showed that sFRP2 enhanced the Wnt3a-mediated transcriptional up-regulation of several genes regulated by Wnt3a including its antagonists, DKK1, and Naked cuticle-1 homolog (NKD1). These results support sFRP2's role as an enhancer of Wnt/β-catenin signaling, a result with biological impact for both normal development and diverse pathologies such as tumorigenesis.

Related: Signal Transduction CTNNB1 gene


Huang Y, Chang X, Lee J, et al.
Cigarette smoke induces promoter methylation of single-stranded DNA-binding protein 2 in human esophageal squamous cell carcinoma.
Int J Cancer. 2011; 128(10):2261-73 [PubMed] Free Access to Full Article Related Publications
Esophageal squamous cell carcinoma (ESCC) is the sixth most frequent cause of cancer death in the world, and cigarette smoke is a key factor in esophageal carcinogenesis. To identify molecular changes during cigarette smoke-induced ESCC, we examined the methylation status of 13 gene promoters in the human immortalized, nontumorigenic esophageal epithelial cell line (Het-1A) that were exposed to mainstream (MSE) or sidestream cigarette smoke extract (SSE) for 6 months in culture. The promoter of sequence-specific single-stranded DNA-binding protein 2 (SSBP2) was methylated in the Het-1A cells exposed to MSE (MSE-Het-1A). Promoter methylation (86%, 56/70) and downregulation of SSBP2 expression were frequently detected in tumor tissues from ESCC patients. In addition, reintroduction of SSBP2 in an ESCC cell line (TE1) that does not express SSBP2 and in the MSE-Het-1A cells inhibited expression of LRP6 and Dvl3, which are mediators of the Wnt signaling pathway. SSBP2 expression markedly decreased the colony-forming ability of ESCC cell lines and significantly inhibited cell growth of the MSE-Het-1A cells. Our results indicate that cigarette smoking is a cause of SSBP2 promoter methylation and that SSBP2 harbors a tumor suppressive role in ESCC through inhibition of the Wnt signaling pathway.

Related: Cancer of the Esophagus Esophageal Cancer


Liu CC, Prior J, Piwnica-Worms D, Bu G
LRP6 overexpression defines a class of breast cancer subtype and is a target for therapy.
Proc Natl Acad Sci U S A. 2010; 107(11):5136-41 [PubMed] Free Access to Full Article Related Publications
The Wnt/beta-catenin signaling pathway is activated in breast cancer, a leading cause of cancer mortality in women. Because mutations in the key intracellular components of this pathway are rare, identifying the molecular mechanisms of aberrant Wnt activation in breast cancer is critical for development of pathway-targeted therapy. Here, we show that expression of the Wnt signaling coreceptor LRP6 is up-regulated in a subpopulation of human breast cancers. LRP6 silencing in breast cancer cells reduces Wnt signaling, cell proliferation, and in vivo tumor growth. In vivo administration of an LRP6 antagonist, Mesd, markedly suppressed growth of MMTV-Wnt1 tumors without causing undesirable side effects. These results demonstrate that Wnt activation at the cell surface contributes to breast cancer tumorigenesis. Together, our studies highlight LRP6 as a potential therapeutic target in breast cancer, and introduce Mesd as a promising antitumor agent for treating breast cancer subtypes with Wnt activation at the cell surface.

Related: Breast Cancer Signal Transduction CTNNB1 gene


Zhang J, Li Y, Liu Q, et al.
Wnt signaling activation and mammary gland hyperplasia in MMTV-LRP6 transgenic mice: implication for breast cancer tumorigenesis.
Oncogene. 2010; 29(4):539-49 [PubMed] Free Access to Full Article Related Publications
Although Wnt signaling activation is frequently observed in human breast cancer, mutations in genes encoding intracellular components of the Wnt signaling pathway are rare. We found that the expression of Wnt signaling co-receptor, LRP6, is upregulated in a subset of human breast cancer tissues and cell lines. To examine whether the overexpression of LRP6 in mammary epithelial cells is sufficient to activate Wnt signaling and promote cell proliferation, we generated transgenic mice overexpressing LRP6 in mammary epithelial cells driven by the mouse mammary tumor virus (MMTV) promoter. We found that mammary glands from MMTV-LRP6 mice exhibit significant Wnt activation evidenced by the translocation of beta-catenin from membrane to cytoplasmic/nuclear fractions. The expression of several Wnt target genes including Axin2, Cyclin D1 and c-Myc was also increased in MMTV-LRP6 mice. More importantly, mammary glands from virgin MMTV-LRP6 mice exhibit significant hyperplasia, a precursor to breast cancer, when compared with wild-type littermate controls. Several matrix metalloproteinases are upregulated in MMTV-LRP6 mice that could contribute to the hyperplasia phenotype. Our results suggest that Wnt signaling activation at the cell-surface receptor level can contribute to breast cancer tumorigenesis.

Related: Signal Transduction


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Cite this page: Cotterill SJ. LRP6, Cancer Genetics Web: http://www.cancerindex.org/geneweb/LRP6.htm Accessed: date

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