Gene Summary

Gene:LRP5; low density lipoprotein receptor-related protein 5
Aliases: HBM, LR3, OPS, EVR1, EVR4, LRP7, OPPG, BMND1, LRP-5, OPTA1, VBCH2
Summary:This gene encodes a transmembrane low-density lipoprotein receptor that binds and internalizes ligands in the process of receptor-mediated endocytosis. This protein also acts as a co-receptor with Frizzled protein family members for transducing signals by Wnt proteins and was originally cloned on the basis of its association with type 1 diabetes mellitus in humans. This protein plays a key role in skeletal homeostasis and many bone density related diseases are caused by mutations in this gene. Mutations in this gene also cause familial exudative vitreoretinopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:low-density lipoprotein receptor-related protein 5
Source:NCBIAccessed: 27 February, 2015


What does this gene/protein do?
Show (39)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 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.

  • TCF Transcription Factors
  • Multiple Abnormalities
  • Brain Stem Glioma, Childhood
  • Intercellular Signaling Peptides and Proteins
  • Neoplasm Invasiveness
  • Cancer Gene Expression Regulation
  • Low Density Lipoprotein Receptor-Related Protein-6
  • beta Catenin
  • Eye Abnormalities
  • Vitreous Body
  • Base Sequence
  • Adolescents
  • Gene Expression Profiling
  • Fetal Blood
  • cdc25 Phosphatases
  • Proto-Oncogene Proteins
  • Exons
  • Low Density Lipoprotein Receptor-Related Protein-5
  • Brain and CNS Tumours
  • Tumor Markers
  • Western Blotting
  • Wnt Proteins
  • Cell Line
  • LDL-Receptor Related Proteins
  • Mutation
  • Cell Proliferation
  • Frizzled Receptors
  • Hyperplasia
  • Signal Transduction
  • Immunohistochemistry
  • Osteoporosis
  • Reproducibility of Results
  • Pedigree
  • Cell Movement
  • Transfection
  • Cell Surface Receptors
  • Lens, Crystalline
  • Childhood Cancer
  • Chromosome 11
  • Bone Cancer
Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

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

Latest Publications: LRP5 (cancer-related)

Farkas SA, Vymetalkova V, Vodickova L, et al.
DNA methylation changes in genes frequently mutated in sporadic colorectal cancer and in the DNA repair and Wnt/β-catenin signaling pathway genes.
Epigenomics. 2014; 6(2):179-91 [PubMed] Related Publications
AIM: The onset and progression of colorectal cancer (CRC) involves a cascade of genetic and/or epigenetic events. The aim of the present study was to address the DNA methylation status of genes relevant in colorectal carcinogenesis and its progression, such as genes frequently mutated in CRC, genes involved in the DNA repair and Wnt signaling pathway.
MATERIAL & METHODS: We analyzed methylation status in totally 160 genes in 12 paired colorectal tumors and adjacent healthy mucosal tissues using the Illumina Infinium Human Methylation 450 BeadChip.
RESULTS: We found significantly aberrant methylation in 23 genes (NEIL1, NEIL3, DCLRE1C, NHEJ1, GTF2H5, CCNH, CTNNB1, DKK2, DKK3, FZD5 LRP5, TLE3, WNT2, WNT3A, WNT6, TCF7L1, CASP8, EDNRB1, GPC6, KIAA1804, MYO1B, SMAD2 and TTN). External validation by mRNA expression showed a good agreement between hypermethylation in cancer and down-regulated mRNA expression of the genes EDNRB1, GPC6 and SMAD2, and between hypomethylation and up-regulated mRNA expression of the CASP8 and DCLRE1C genes.
CONCLUSION: Aberrant methylation of the DCLRE1C and GPC6 genes are presented here for the first time and are therefore of special interest for further validation as novel candidate biomarker genes in CRC, and merit further validation with specific assays.

Cnossen WR, te Morsche RH, Hoischen A, et al.
Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis.
Proc Natl Acad Sci U S A. 2014; 111(14):5343-8 [PubMed] Free Access to Full Article Related Publications
Polycystic livers are seen in the rare inherited disorder isolated polycystic liver disease (PCLD) and are recognized as the most common extrarenal manifestation in autosomal dominant polycystic kidney disease. Hepatic cystogenesis is characterized by progressive proliferation of cholangiocytes, ultimately causing hepatomegaly. Genetically, polycystic liver disease is a heterogeneous disorder with incomplete penetrance and caused by mutations in PRKCSH, SEC63, PKD1, or PKD2. Genome-wide SNP typing and Sanger sequencing revealed no pathogenic variants in hitherto genes in an extended PCLD family. We performed whole-exome sequencing of DNA samples from two members. A heterozygous variant c.3562C > T located at a highly conserved amino acid position (p.R1188W) in the low density lipoprotein receptor-related protein 5 (LRP5) gene segregated with the disease (logarithm of odds score, 4.62) but was not observed in more than 1,000 unaffected individuals. Screening of LRP5 in a PCLD cohort identified three additional mutations in three unrelated families with polycystic livers (p.V454M, p.R1529S, and p.D1551N), again all undetected in controls. All variants were predicted to be damaging with profound structural effects on LRP5 protein domains. Liver cyst tissue and normal hepatic tissue samples from patients and controls showed abundant LRP5 expression by immunohistochemistry. Functional activity analyses indicated that mutant LRP5 led to reduced wingless signal activation. In conclusion, we demonstrate that germ-line LRP5 missense mutations are associated with hepatic cystogenesis. The findings presented in this study link the pathophysiology of PCLD to deregulation of the canonical wingless signaling pathway.

Rabbani SA, Arakelian A, Farookhi R
LRP5 knockdown: effect on prostate cancer invasion growth and skeletal metastasis in vitro and in vivo.
Cancer Med. 2013; 2(5):625-35 [PubMed] Free Access to Full Article Related Publications
Prostate cancer (PCa) is a common hormone-dependent malignancy associated with the development of skeletal metastases. This is due to the increased expression of a number of growth factors, cytokines, and proteases which collectively drive the metastatic cascade in general and increased propensity to develop skeletal metastasis in particular. While a number of signaling pathways have been implicated in PCa progression, the highly complex wnt/β-catenin pathway is unique due to its ability to regulate gene expression, cell invasion, migration, survival, proliferation, and differentiation to contribute in the initiation and progression of PCa. Members of the wnt family bind to the Frizzle proteins or lipoprotein-related receptor proteins 5, 6 (LRP5, -6) to activate this key pathway. In the current study, we have investigated the role of wnt/β-catenin pathway in PCa progression, skeletal metastasis, and gene expression using the dominant negative plasmid of LRP5 (DN-LRP5) and human PCa cells PC-3. Inactivation of LRP5 resulted in mesenchymal to epithelial shift, lack of translocation of β-catenin to cell surface, increased tumor cell proliferation, decreased colony formation, migration and invasion in vitro. These effects were attributed to decreased expression of pro-invasive and pro-metastatic genes. In in vivo studies, PC-3-DN-LRP5 cells developed significantly smaller tumors and a marked decrease in skeletal lesion area and number as determined by X-ray, micro (μ) CT and histological analysis. Collectively results from these studies demonstrate the dominant role of this key pathway in PCa growth and skeletal metastasis and its potential as a viable therapeutic target.

Shi ZZ, Jiang YY, Hao JJ, et al.
Identification of putative target genes for amplification within 11q13.2 and 3q27.1 in esophageal squamous cell carcinoma.
Clin Transl Oncol. 2014; 16(7):606-15 [PubMed] Related Publications
BACKGROUND: Genomic aberration is a common feature of human cancers and also is one of the basic mechanisms that lead to overexpression of oncogenes and underexpression of tumor suppressor genes. Our study aims to identify frequent genomic changes and candidate copy number driving genes in esophageal squamous cell carcinoma (ESCC).
METHODS: We used array comparative genomic hybridization to identify recurrent genomic alterations and screened the candidate targets of selected amplification regions by quantitative and semi-quantitative RT-PCR.
RESULTS: Thirty-four gains and 16 losses occurred in more than 50 % of ESCCs. High-level amplifications at 7p11.2, 8p12, 8q24.21, 11q13.2-q13.3, 12p11.21, 12q12 and homozygous deletions at 2q22.1, 8p23.1-p21.2, 9p21.3 and 14q11.2 were also identified. 11q13.2 was a frequent amplification region, in which five genes including CHKA, GAL, KIAA1394, LRP5 and PTPRCAP were overexpressed in tumor tissues than paracancerous normal tissues. The expression of ALG3 at 3q27.1 was higher in ESCCs, especially in patients with lymph node metastasis.
CONCLUSIONS: Target gene identification of amplifications or homozygous deletions will help to reveal the mechanism of tumor formation and explore new therapy method.

Wu XQ, Huang C, He X, et al.
Feedback regulation of telomerase reverse transcriptase: new insight into the evolving field of telomerase in cancer.
Cell Signal. 2013; 25(12):2462-8 [PubMed] Related Publications
Telomerase reverse transcriptase (TERT) is the catalytic component of telomerase, especially the rate-limiting determinant of telomerase activity. So far, TERT has been reported to be over-expressed in more than 90% of cancers, thereby playing a critical role in sustained proliferation and survival potentials of various cancer cells. Over the past decade, a comprehensive network of transcription factors has been shown to be involved in the regulation of TERT. Furthermore, accumulating evidence has suggested that TERT could modulate the expression of numerous genes involved in diverse group of cellular processes, including cell cycle regulation and cellular signaling. Therefore, it indicates that TERT is both an effector and a regulator in carcinoma. However, the mechanisms of the interaction between TERT and its target genes are still not fully understood. Thus, it is necessary to consolidate and summarize recent developments of the cross-talk between TERT and related genes in cancer cells or other cells with cancer cell characteristics, and elucidate these relevant mechanisms. In this review, we focus on various signaling pathways and genes that participate in the feedback regulation of TERT and the underlying feedback loop mechanism of TERT, further providing new insights into non-telomeric functions of telomerase and potentially to be used as a novel therapeutic target for cancer.

Knoblich K, Wang HX, Sharma C, et al.
Tetraspanin TSPAN12 regulates tumor growth and metastasis and inhibits β-catenin degradation.
Cell Mol Life Sci. 2014; 71(7):1305-14 [PubMed] Related Publications
Ablation of tetraspanin protein TSPAN12 from human MDA-MB-231 cells significantly decreased primary tumor xenograft growth, while increasing tumor apoptosis. Furthermore, TSPAN12 removal markedly enhanced tumor-endothelial interactions and increased metastasis to mouse lungs. TSPAN12 removal from human MDA-MB-231 cells also caused diminished association between FZD4 (a key canonical Wnt pathway receptor) and its co-receptor LRP5. The result likely explains substantially enhanced proteosomal degradation of β-catenin, a key effecter of canonical Wnt signaling. Consistent with disrupted canonical Wnt signaling, TSPAN12 ablation altered expression of LRP5, Naked 1 and 2, DVL2, DVL3, Axin 1, and GSKβ3 proteins. TSPAN12 ablation also altered expression of several genes regulated by β-catenin (e.g. CCNA1, CCNE2, WISP1, ID4, SFN, ME1) that may help to explain altered tumor growth and metastasis. In conclusion, these results provide the first evidence for TSPAN12 playing a role in supporting primary tumor growth and suppressing metastasis. TSPAN12 appears to function by stabilizing FZD4-LRP5 association, in support of canonical Wnt-pathway signaling, leading to enhanced β-catenin expression and function.

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.

Qu Y, Dang S, Hou P
Gene methylation in gastric cancer.
Clin Chim Acta. 2013; 424:53-65 [PubMed] Related Publications
Gastric cancer is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. Over 70% of new cases and deaths occur in developing countries. In the early years of the molecular biology revolution, cancer research mainly focuses on genetic alterations, including gastric cancer. Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer, including DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs, and microRNAs. Aberrant DNA methylation in the promoter regions of gene, which leads to inactivation of tumor suppressor and other cancer-related genes in cancer cells, is the most well-defined epigenetic hallmark in gastric cancer. The advantages of gene methylation as a target for detection and diagnosis of cancer in biopsy specimens and non-invasive body fluids such as serum and gastric washes have led to many studies of application in gastric cancer. This review focuses on the most common and important phenomenon of epigenetics, DNA methylation, in gastric cancer and illustrates the impact epigenetics has had on this field.

Li T, Zhao H, Hung GC, et al.
Differentially expressed genes and pathways induced by organophosphates in human neuroblastoma cells.
Exp Biol Med (Maywood). 2012; 237(12):1413-23 [PubMed] Related Publications
Organophosphates (OPs) are toxic chemicals commonly used as pesticides and herbicides. Some OPs are highly toxic to humans and have been used in warfare and terrorist attacks. In order to elucidate the molecular mechanisms of injury caused by OPs, the differentially expressed genes were analyzed in human SK-N-SH neuroblastoma cells induced by three OPs. The SK-N-SH cells were treated with one of the three OPs, chlorpyrifos, dichlorvos or methamidophos at LC20 (high-dose), the concentration causing 20% cell death, as well as 1/20 of LC20 (low-dose), a sub-lethal concentration with no detectable cell death, for 24 h. The genome-wide gene changes were identified by Agilent Microarray System, and analyzed by microarray analysis tools. The analysis revealed neuroblastoma cells treated with the high doses of all three OPs markedly activated cell apoptosis and inhibited cell growth and proliferation genes, which would most likely lead to the process of cell death. Interestingly, the analysis also revealed significant decrease in expressions of many genes in a specific spliceosome pathway in cells treated with the low doses of all three different OPs. The change of spliceosome pathway may represent an important mechanism of injury in neuronal cells exposed to low doses of various OPs. In addition to unraveling a potentially different form of OP pathogenesis, this finding could provide a new diagnostic marker in assessing OP-associated injury in cells or tissues. In addition, these results could also contribute to the development of new prevention and/or therapeutic regimens against OP toxicity.

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.

Wang K, Li N, Yeung CH, et al.
Oncogenic Wnt/β-catenin signalling pathways in the cancer-resistant epididymis have implications for cancer research.
Mol Hum Reprod. 2013; 19(2):57-71 [PubMed] Related Publications
Aberrant activation of the Wnt/β-catenin pathway occurs in cancers. This review presents several important cancer-related aspects of Wnt/β-catenin signalling relevant to the epididymis, provides evidence of such epididymal gene expression and suggests a new direction for further research. The data presented here indicate that besides containing many Wnt/β-catenin-pathway components, the normal adult human epididymis expresses much more β-catenin than the colorectal carcinoma cell line HCT116, which possesses elevated β-catenin expression. The low cancer incidence in the epididymis may be due to factors present in the human epididymis that regulate this oncogenic Wnt/β-catenin pathway, including (i) 14 of 17 secreted pathway inhibitors, (ii) the majority of the micro-RNAs known to target this pathway, (iii) plasma membrane-associated E-cadherin and CEACAM1 that anchor β-catenin, preventing its availability for nuclear entry and oncogenic transcriptional activity, (iv) the recently identified membrane-located tumourigenesis inhibitors RNF43 and ZNRF3 that mediate the degradation of the Wnt receptor components Fzds and Lrp5/6 and (v) nuclear KLF4, which competes with TCF for β-catenin, limiting its transcriptional activity and stabilizing telomeres, thereby reducing mutation incidence. The above regulatory factors expressed by the human epididymis, and the absence of androgen receptor translocation known to promote nuclear translocation of β-catenin in tumourigenesis in an animal model, may act synergistically to provide hostility in different cell compartments towards tumour formation. The lack of evidence for β-catenin in epididymal nuclei is noteworthy. Studying this phenomenon may help reveal the mechanisms underlying oncogenic Wnt/β-catenin signalling and shed new light on cancer therapy and prevention.

Starker LF, Fonseca AL, Fonseca A, et al.
Evidence of a stabilizing mutation of β-catenin encoded by CTNNB1 exon 3 in a large series of sporadic parathyroid adenomas.
Endocrine. 2012; 42(3):612-5 [PubMed] Related Publications
Aberrant accumulation of β-catenin plays an important role in a variety of human neoplasms. This can be caused by stabilizing mutation of β-catenin (CTNNB1, exon 3) or by mutation or deregulated expression of other components of the WNT/β-catenin signaling pathway. Accumulation of non-phosphorylated active β-catenin has been reported to commonly occur in parathyroid adenomas from patients with primary hyperparathyroidism (pHPT), either due to the aberrantly spliced internally truncated WNT receptor LRP5 (LRP5Δ) or to a stabilizing mutation of β-catenin. The S37A mutation was reported to occur in 7.3 % in a single study of parathyroid adenomas, while in other studies no stabilizing mutations of β-catenin exon 3 were identified. The aim of this study was to determine the mutational frequency of the CTNNB1 gene, specifically exon 3 in a large series of parathyroid adenomas. One hundred and eighty sporadic parathyroid adenomas were examined for mutations in exon 3 of CTNNB1 by direct DNA sequencing, utilizing previously published primer sequences. The mutation S33C (TCT>TGT) was detected by direct-DNA sequencing of PCR fragments in 1 out of 180 sporadic parathyroid adenomas (0.68 %). Like serine 37, mutations of serine 33 have been reported in many neoplasms with resulting β-catenin stabilization, enhanced transcription, and oncogenic activities. Immunohistochemical analysis revealed an overexpression of the β-catenin protein in the lone mutant tumor. Taking also previous studies into account we conclude that activating mutations of the regulatory GSK-3β phosphorylation sites serine 33 and 37, encoded by CTNNB1 exon 3, rarely occur in parathyroid adenomas from patients with pHPT.

Herencia C, Martínez-Moreno JM, Herrera C, et al.
Nuclear translocation of β-catenin during mesenchymal stem cells differentiation into hepatocytes is associated with a tumoral phenotype.
PLoS One. 2012; 7(4):e34656 [PubMed] Free Access to Full Article Related Publications
Wnt/β-catenin pathway controls biochemical processes related to cell differentiation. In committed cells the alteration of this pathway has been associated with tumors as hepatocellular carcinoma or hepatoblastoma. The present study evaluated the role of Wnt/β-catenin activation during human mesenchymal stem cells differentiation into hepatocytes. The differentiation to hepatocytes was achieved by the addition of two different conditioned media. In one of them, β-catenin nuclear translocation, up-regulation of genes related to the Wnt/β-catenin pathway, such as Lrp5 and Fzd3, as well as the oncogenes c-myc and p53 were observed. While in the other protocol there was a Wnt/β-catenin inactivation. Hepatocytes with nuclear translocation of β-catenin also had abnormal cellular proliferation, and expressed membrane proteins involved in hepatocellular carcinoma, metastatic behavior and cancer stem cells. Further, these cells had also increased auto-renewal capability as shown in spheroids formation assay. Comparison of both differentiation protocols by 2D-DIGE proteomic analysis revealed differential expression of 11 proteins with altered expression in hepatocellular carcinoma. Cathepsin B and D, adenine phosphoribosyltransferase, triosephosphate isomerase, inorganic pyrophosphatase, peptidyl-prolyl cis-trans isomerase A or lactate dehydrogenase β-chain were up-regulated only with the protocol associated with Wnt signaling activation while other proteins involved in tumor suppression, such as transgelin or tropomyosin β-chain were down-regulated in this protocol. In conclusion, our results suggest that activation of the Wnt/β-catenin pathway during human mesenchymal stem cells differentiation into hepatocytes is associated with a tumoral phenotype.

Almeida MQ, Azevedo MF, Xekouki P, et al.
Activation of cyclic AMP signaling leads to different pathway alterations in lesions of the adrenal cortex caused by germline PRKAR1A defects versus those due to somatic GNAS mutations.
J Clin Endocrinol Metab. 2012; 97(4):E687-93 [PubMed] Free Access to Full Article Related Publications
CONTEXT: The overwhelming majority of benign lesions of the adrenal cortex leading to Cushing syndrome are linked to one or another abnormality of the cAMP or protein kinase pathway. PRKAR1A-inactivating mutations are responsible for primary pigmented nodular adrenocortical disease, whereas somatic GNAS activating mutations cause macronodular disease in the context of McCune-Albright syndrome, ACTH-independent macronodular hyperplasia, and, rarely, cortisol-producing adenomas.
OBJECTIVE AND DESIGN: The whole-genome expression profile (WGEP) of normal (pooled) adrenals, PRKAR1A- (3) and GNAS-mutant (3) was studied. Quantitative RT-PCR and Western blot were used to validate WGEP findings.
RESULTS: MAPK and p53 signaling pathways were highly overexpressed in all lesions against normal tissue. GNAS-mutant tissues were significantly enriched for extracellular matrix receptor interaction and focal adhesion pathways when compared with PRKAR1A-mutant (fold enrichment 3.5, P < 0.0001 and 2.1, P < 0.002, respectively). NFKB, NFKBIA, and TNFRSF1A were higher in GNAS-mutant tumors (P < 0.05). Genes related to the Wnt signaling pathway (CCND1, CTNNB1, LEF1, LRP5, WISP1, and WNT3) were overexpressed in PRKAR1A-mutant lesions.
CONCLUSION: WGEP analysis revealed that not all cAMP activation is the same: adrenal lesions harboring PRKAR1A or GNAS mutations share the downstream activation of certain oncogenic signals (such as MAPK and some cell cycle genes) but differ substantially in their effects on others.

Lee DY, Cho TJ, Lee HR, et al.
Disturbed osteoblastic differentiation of fibrous hamartoma cell from congenital pseudarthrosis of the tibia associated with neurofibromatosis type I.
Clin Orthop Surg. 2011; 3(3):230-7 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Fibrous hamartoma is the key pathology of congenital pseudarthrosis of the tibia (CPT), which was shown to have low osteogenicity and high osteoclastogenicity. This study further investigated the mechanism of impaired osteoblastic differentiation of fibrous hamartoma cells.
METHODS: Fibroblast-like cells were obtained from enzymatically dissociated fibrous hamartomas of 11 patients with CPT associated with neurofibromatosis type I (NF1). Periosteal cells were also obtained from the distal tibial periosteum of 3 patients without CPT or NF1 as control. The mRNA levels of Wnt ligands and their canonical receptors, such as Lrp5 and β-catenin, were assayed using reverse transcriptase PCR (RT-PCR). Changes in mRNA expression of osteoblast marker genes by rhBMP2 treatment were assayed using quantitative real time RT-PCR. Changes in mRNA expression of transcription factors specifically involved in osteoblastic differentiation by rhBMP2 treatment was also assayed using quantitative real-time RT-PCR.
RESULTS: Wnt1 and Wnt3a mRNA expression was lower in fibrous hamartoma than in tibial periosteal cells, but their canonical receptors did not show significant difference. Response of osteoblastic marker gene expression to rhBMP2 treatment showed patient-to-patient variability. Col1a1 mRNA expression was up-regulated in most fibrous hamartoma tissues, osteocalcin was up-regulated in a small number of patients, and ALP expression was down-regulated in most fibrous hamartoma tissues. Changes in mRNA expression of the transcription factors in response to rhBMP2 also showed factor-to-factor and patient-to-patient variability. Dlx5 was consistently up-regulated by rhBMP2 treatment in all fibrous hamartoma tissues tested. Msx2 expression was down-regulated by rhBMP2 in most cases but by lesser extent than control tissue. Runx2 expression was up-regulated in 8 out of 18 fibrous hamartoma tissues tested. Osterix expression was up-regulated in 2 and down-regulated in 3 fibrous hamartoma tissues.
CONCLUSIONS: Congenital pseudarthrosis of the tibia appears to be caused by fibrous hamartoma originating from aberrant growth of Nf1 haploinsufficient periosteal cells, which failed in terminal osteoblastic differentiation and arrested at a certain stage of this process. This pathomechanism of CPT should be targeted in the development of novel therapeutic biologic intervention.

Vijayakumar S, Liu G, Rus IA, et al.
High-frequency canonical Wnt activation in multiple sarcoma subtypes drives proliferation through a TCF/β-catenin target gene, CDC25A.
Cancer Cell. 2011; 19(5):601-12 [PubMed] Free Access to Full Article Related Publications
Wnt canonical signaling is critical for normal development as well as homeostasis of several epithelial tissues, and constitutive activation of this pathway is commonly observed in carcinomas. We show here that 50% of human sarcomas (n = 45) and 65% of sarcoma cell lines (n = 23) of diverse histological subtypes exhibit upregulated autocrine canonical Wnt signaling. Furthermore, in Wnt autocrine cell lines, we identify alterations including overexpression or gene amplification of Wnt ligands and/or LRP5/6 coreceptors and epigenetic silencing of different cell surface Wnt antagonists. Mutations in adenomatous polyposis coli (APC) gene were observed in two nonautocrine Wnt-positive sarcoma cell lines. Finally, downregulation of the activated Wnt pathway inhibited sarcoma cell proliferation both in vitro and in vivo by a mechanism involving the downregulation of CDC25A.

Kim S, Goel S, Alexander CM
Differentiation generates paracrine cell pairs that maintain basaloid mouse mammary tumors: proof of concept.
PLoS One. 2011; 6(4):e19310 [PubMed] Free Access to Full Article Related Publications
There is a paradox offered up by the cancer stem cell hypothesis. How are the mixed populations that are characteristic of heterogeneous solid tumors maintained at constant proportion, given their high, and different, mitotic indices? In this study, we evaluate a well-characterized mouse model of human basaloid tumors (induced by the oncogene Wnt1), which comprise mixed populations of mammary epithelial cells resembling their normal basal and luminal counterparts. We show that these cell types are substantially inter-dependent, since the MMTV LTR drives expression of Wnt1 ligand in luminal cells, whereas the functional Wnt1-responsive receptor (Lrp5) is expressed by basal cells, and both molecules are necessary for tumor growth. There is a robust tumor initiating activity (tumor stem cell) in the basal cell population, which is associated with the ability to differentiate into luminal and basal cells, to regenerate the oncogenic paracrine signaling cell pair. However, we found an additional tumor stem cell activity in the luminal cell population. Knowing that tumors depend upon Wnt1-Lrp5, we hypothesized that this stem cell must express Lrp5, and found that indeed, all the stem cell activity could be retrieved from the Lrp5-positive cell population. Interestingly, this reflects post-transcriptional acquisition of Lrp5 protein expression in luminal cells. Furthermore, this plasticity of molecular expression is reflected in plasticity of cell fate determination. Thus, in vitro, Wnt1-expressing luminal cells retro-differentiate to basal cell types, and in vivo, tumors initiated with pure luminal cells reconstitute a robust basal cell subpopulation that is indistinguishable from the populations initiated by pure basal cells. We propose this is an important proof of concept, demonstrating that bipotential tumor stem cells are essential in tumors where oncogenic ligand-receptor pairs are separated into different cell types, and suggesting that Wnt-induced molecular and fate plasticity can close paracrine loops that are usually separated into distinct cell types.

Toiviainen-Salo S, Linnankivi T, Saarinen A, et al.
Cerebroretinal microangiopathy with calcifications and cysts: characterization of the skeletal phenotype.
Am J Med Genet A. 2011; 155A(6):1322-8 [PubMed] Related Publications
Cerebral cysts and calcifications with leukoencephalopathy and retinal vascular abnormalities are diagnostic hallmarks of cerebroretinal microangiopathy with calcifications and cysts (CRMCC). Previous studies have suggested that skeletal involvement is also common, but its characteristics remain unknown. This study aimed to assess the skeletal phenotype in CRMCC. All Finnish patients with features consistent with CRMCC and for whom radiographs were available were included. Clinical information pertinent to the skeletal phenotype was collected from hospital records, and all plain radiographs were reviewed for skeletal features. Bone mineral density (BMD) was measured by DXA. In one patient, bone biopsies were obtained for bone histology and histomorphometric analyses. The LRP5 gene was analyzed for mutations by direct sequencing. Our results show that the skeletal phenotype in CRMCC includes (1) compromised longitudinal growth pre- and postnatally, (2) generalized osteopenia or early onset low turnover osteoporosis with fragility fractures, and (3) metaphyseal abnormalities that may lead to limb deformities such as short femoral neck or genua valga. DXA measurements in three patients showed low BMD, and bone biopsies in the fourth patient with pathological fractures and impaired fracture healing showed low-turnover osteoporosis, with reduced osteoclast and osteoblast activity. Direct sequencing of all LRP5 coding exons and exon-intron boundaries in six patients with CRMCC revealed no putative mutations. We conclude that the CRMCC-associated bone disease is characterized by low BMD and pathological fractures with delayed healing, metaphyseal changes, and short stature pre- and postnatally. LRP5 is not a disease-causing gene in CRMCC.

Liu Y, Zhou ZT, He QB, Jiang WW
DAPK promoter hypermethylation in tissues and body fluids of oral precancer patients.
Med Oncol. 2012; 29(2):729-33 [PubMed] Related Publications
Death-associated protein kinase (DAPK) has been suggested as a tumor suppressor gene. A high frequency of DAPK promoter hypermethylation has been noted in head and neck cancers and other solid tumors, and it has been used as a tumor marker in molecular detection strategies. Our aim was to examine DAPK promoter hypermethylation in tissue, blood, and salivary rinse samples of oral precancer patients (OPs) and to explore the potential role in oral carcinogenesis. DAPK hypermethylation was analyzed in 77 OPs and 32 oral squamous cell carcinomas (OSCCs) by real-time quantitative methylation-specific PCR (QMSP). We compared the hypermethylation expression between two groups and analyzed the associations with clinicopathologic parameters. The promoter hypermethylation frequency of DAPK in tissue (46.9%) and blood (52.2%) of OSCCs was significantly higher than those in OPs (19.5%, P = 0.004; 22.4%, P = 0.007, respectively). DAPK promoter hypermethylation expression in blood was correlated with its expression in tissue (r = 0.49, P < 0.000). The OP patients who smoked more than 20 years were found 40.0% tissue DAPK hypermethylation in contrast with 10.7% tissue DAPK hypermethylation in the patients whose smoking duration ≦20 years (P = 0.010). Our results suggest that DAPK hypermethylation is an early event in oral carcinogenesis and blood DAPK hypermethylation might be a potential minimal invasive biomarker for OSCC early detection.

Dai W, Teodoridis JM, Zeller C, et al.
Systematic CpG islands methylation profiling of genes in the wnt pathway in epithelial ovarian cancer identifies biomarkers of progression-free survival.
Clin Cancer Res. 2011; 17(12):4052-62 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Wnt pathways control key biological processes that potentially impact on tumor progression and patient survival. We aimed to evaluate DNA methylation at promoter CpG islands (CGI) of Wnt pathway genes in ovarian tumors at presentation and identify biomarkers of patient progression-free survival (PFS).
EXPERIMENTAL DESIGN: Epithelial ovarian tumors (screening study n = 120, validation study n = 61), prospectively collected through a cohort study, were analyzed by differential methylation hybridization at 302 loci spanning 189 promoter CGIs at 137 genes in Wnt pathways. The association of methylation and PFS was examined by Cox proportional hazards model.
RESULTS: DNA methylation is associated with PFS at 20 of 302 loci (P < 0.05, n = 111), with 5 loci significant at false discovery rate (FDR) less than 10%. A total of 11 of 20 loci retain significance in an independent validation cohort (n = 48, P ≤ 0.05, FDR ≤ 10%), and 7 of these loci, at FZD4, DVL1, NFATC3, ROCK1, LRP5, AXIN1, and NKD1 genes, are independent from clinical parameters (adjusted P < 0.05). Increased methylation at these loci associates with increased hazard of disease progression. A multivariate Cox model incorporates only NKD1 and DVL1, identifying two groups differing in PFS [HR = 2.09; 95% CI (1.39-3.15); permutation test P < 0.005]. Methylation at DVL1 and NFATC3 show significant association with response. Consistent with their epigenetic regulation, reduced expression of FZD4, DVL1, and ROCK1 is an indicator of early-disease relapse in an independent ovarian tumor cohort (n = 311, adjusted P < 0.05).
CONCLUSION: The data highlight the importance of epigenetic regulation of multiple promoter CGIs of Wnt pathway genes in ovarian cancer and identify methylation at NKD1 and DVL1 as independent predictors of PFS.

Annabi B, Doumit J, Plouffe K, et al.
Members of the low-density lipoprotein receptor-related proteins provide a differential molecular signature between parental and CD133+ DAOY medulloblastoma cells.
Mol Carcinog. 2010; 49(7):710-7 [PubMed] Related Publications
Members of the low-density lipoprotein receptor-related protein (LRP) family are involved in metabolic stress and resistance phenotypes of cancer cells. New breakthroughs in brain cancer therapy have exploited that molecular signature and proved that efficient delivery of therapeutic agents involve LRP-mediated mechanisms. We performed gene expression profiling of CD133, a cell surface cancer stem cell marker, and of LRP in response to in vitro nutrient deprivation. We found that CD133 was selectively induced in serum-starved DAOY medulloblastoma cells but not in U87MG glioblastoma cells. Such CD133 induction was correlated to increases in LRP-1 and LRP-1b gene and protein expression. When a specific CD133(+) DAOY cell population was sorted from parental DAOY, we found increases in LRP-5 and LRP-8. Uptake of alpha(2)-macroglobulin, a specific LRP-1/1b ligand, was increased in serum-starved parental DAOY cells but not in CD133(+) DAOY cells, and receptor-associated protein (RAP), which binds to all cell surface LRPs, was able to compete for that uptake. Conversely, RAP binding was increased in serum-starved parental DAOY but alpha(2)-macroglobulin was unable to compete for such uptake. Strategies aiming at targeting cancer stem cell metabolic adaptative responses, such as that through LRP differential expression within the brain tissue microenvironmental niche, can now be envisioned.

Narumi S, Numakura C, Shiihara T, et al.
Various types of LRP5 mutations in four patients with osteoporosis-pseudoglioma syndrome: identification of a 7.2-kb microdeletion using oligonucleotide tiling microarray.
Am J Med Genet A. 2010; 152A(1):133-40 [PubMed] Related Publications
Osteoporosis-pseudoglioma syndrome (OPS; OMIM 259770) is an autosomal-recessive genetic disorder characterized by severe osteoporosis and visual disturbance from childhood. Biallelic mutations in the low-density lipoprotein receptor-related protein 5 gene (LRP5) have been frequently detected, while a subset of patients had only one or no detectable mutation. We report on the clinical and molecular findings of four unrelated Japanese patients with the syndrome. The four patients had typical skeletal and ocular phenotypes of OPS, namely severe juvenile osteoporosis and early-onset visual disturbance, with or without mental retardation. We undertook standard PCR-based sequencing for LRP5 and found four missense mutations (p.L145F, p.T244M, p.P382L, and p.T552M), one nonsense mutation (p.R1534X), and one splice site mutation (c.1584+1G>A) among four OPS patients. Although three patients had two heterozygous mutations, one had only one heterozygous splice site mutation. In this patient, RT-PCR from lymphocytic RNA demonstrated splice error resulting in 63-bp insertion between exons 7 and 8. Furthermore, the patient was found to have only mutated RT-PCR fragment, implying that a seemingly normal allele did not express LRP5 mRNA. We then conducted custom- designed oligonucleotide tiling microarray analyses targeted to a 600-kb genome region harboring LRP5 and discovered a 7.2-kb microdeletion encompassing exons 22 and 23 of LRP5. We found various types of LRP5 mutations, including an exon-level deletion that is undetectable by standard PCR-based mutation screening. Oligonucleotide tiling microarray seems to be a powerful tool in identifying cryptic structural mutations.

Yuzugullu H, Benhaj K, Ozturk N, et al.
Canonical Wnt signaling is antagonized by noncanonical Wnt5a in hepatocellular carcinoma cells.
Mol Cancer. 2009; 8:90 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: beta-catenin mutations that constitutively activate the canonical Wnt signaling have been observed in a subset of hepatocellular carcinomas (HCCs). These mutations are associated with chromosomal stability, low histological grade, low tumor invasion and better patient survival. We hypothesized that canonical Wnt signaling is selectively activated in well-differentiated, but repressed in poorly differentiated HCCs. To this aim, we characterized differentiation status of HCC cell lines and compared their expression status of Wnt pathway genes, and explored their activity of canonical Wnt signaling.
RESULTS: We classified human HCC cell lines into "well-differentiated" and "poorly differentiated" subtypes, based on the expression of hepatocyte lineage, epithelial and mesenchymal markers. Poorly differentiated cell lines lost epithelial and hepatocyte lineage markers, and overexpressed mesenchymal markers. Also, they were highly motile and invasive. We compared the expression of 45 Wnt pathway genes between two subtypes. TCF1 and TCF4 factors, and LRP5 and LRP6 co-receptors were ubiquitously expressed. Likewise, six Frizzled receptors, and canonical Wnt3 ligand were expressed in both subtypes. In contrast, canonical ligand Wnt8b and noncanonical ligands Wnt4, Wnt5a, Wnt5b and Wnt7b were expressed selectively in well- and poorly differentiated cell lines, respectively. Canonical Wnt signaling activity, as tested by a TCF reporter assay was detected in 80% of well-differentiated, contrary to 14% of poorly differentiated cell lines. TCF activity generated by ectopic mutant beta-catenin was weak in poorly differentiated SNU449 cell line, suggesting a repressive mechanism. We tested Wnt5a as a candidate antagonist. It strongly inhibited canonical Wnt signaling that is activated by mutant beta-catenin in HCC cell lines.
CONCLUSION: Differential expression of Wnt ligands in HCC cells is associated with selective activation of canonical Wnt signaling in well-differentiated, and its repression in poorly differentiated cell lines. One potential mechanism of repression involved Wnt5a, acting as an antagonist of canonical Wnt signaling. Our observations support the hypothesis that Wnt pathway is selectively activated or repressed depending on differentiation status of HCC cells. We propose that canonical and noncanonical Wnt pathways have complementary roles in HCC, where the canonical signaling contributes to tumor initiation, and noncanonical signaling to tumor progression.

Saarinen A, Saukkonen T, Kivelä T, et al.
Low density lipoprotein receptor-related protein 5 (LRP5) mutations and osteoporosis, impaired glucose metabolism and hypercholesterolaemia.
Clin Endocrinol (Oxf). 2010; 72(4):481-8 [PubMed] Related Publications
OBJECTIVE: Mutations in the low-density lipoprotein receptor-related protein 5 gene (LRP5) underlie osteoporosis-pseudoglioma syndrome. Animal models implicate a role for LRP5 in lipid and glucose homeostasis. The objective was to evaluate metabolic consequences of LRP5 mutations in humans.
DESIGN AND PATIENTS: Thirteen Finnish individuals with homozygous or heterozygous LRP5 mutations were assessed for bone health, glucose and lipid metabolism, and for serum serotonin concentration. Results were compared with findings in family members without mutations.
MEASUREMENTS: Bone mineral density (BMD), vertebral morphology, oral and intravenous glucose tolerance tests, lipid profile and serum serotonin concentrations.
RESULTS: Two individuals were homozygous for R570W, one compound heterozygous for R570W and R1036Q, and 10 were heterozygous (six for R570W, three for R1036Q and one for R925C). Subjects with two LRP5 mutations had multiple spinal fractures and low BMD. Subjects with one mutation had significantly lower median lumbar spine (P = 0.004) and femoral neck (P = 0.005) BMD Z-scores, and more often vertebral fractures than the 18 individuals without mutations. Of the 12 subjects with LRP5 mutation six had diabetes and one had impaired glucose tolerance. Intravenous glucose tolerance tests suggested impaired beta-cell function; no insulin resistance was observed. Prevalence of hypercholesterolaemia was similar in mutation positive and negative subjects. Serum serotonin concentrations showed a trend towards higher concentrations in subjects with LRP5 mutation.
CONCLUSIONS: We found high prevalence of osteoporosis and abnormal glucose metabolism in subjects with LRP5 mutation(s). Further studies are needed to establish the role of LRP5 in glucose and lipid metabolism.

Johnson MW, Rogers GB, Bruce KD, et al.
Bacterial community diversity in cultures derived from healthy and inflamed ileal pouches after restorative proctocolectomy.
Inflamm Bowel Dis. 2009; 15(12):1803-11 [PubMed] Related Publications
BACKGROUND: Pouchitis is believed to occur as a reaction to dysbiosis. In this study we assessed differences between mucosal bacterial communities cultured from noninflamed and inflamed ileal pouches.
METHODS: Thirty-two ileal pouch patients, 22 with ulcerative colitis (UC) and 10 with familial adenomatous polyposis (FAP), underwent symptomatic, endoscopic, and histological assessment. The Objective Pouchitis Score (OPS) and the Pouch Disease Activity Index (PDAI) were used to diagnose pouchitis. Seven UC patients had pouchitis (UC+), 15 had a noninflamed pouch (UC-), 9 had a noninflamed pouch (FAP-), and 1 FAP patient had pouchitis (FAP+). Biopsies taken from the ileal mucosa of the pouch were cultured under aerobic and anaerobic conditions. Following standardized DNA extraction a polymerase chain reaction (PCR) was performed to generate 16S rRNA gene products. A "fingerprint" of the bacterial community within each sample was created using terminal-restriction fragment length polymorphism (T-RFLP) profiling. Species richness and evenness were determined using T-RF band lengths and relative band intensities.
RESULTS: From the 64 DNA samples, 834 bands were detected, of which 179 represented different species (operational taxonomic units [OTUs]). The average species richness for the FAP-, FAP+, UC-, and UC+ groups was 26, 35, 23.9, and 29.6 per patient, with the average species diversity within the groups of 10.6, 29, 8.3, and 11.4, respectively. Similar trends were observed when the anaerobic and aerobic-derived bacterial groups were analyzed separately.
CONCLUSIONS: No significant differences were found between the bacterial cultures derived from any of the clinical groups or between pouchitis and nonpouchitis patients.

Björklund P, Svedlund J, Olsson AK, et al.
The internally truncated LRP5 receptor presents a therapeutic target in breast cancer.
PLoS One. 2009; 4(1):e4243 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Breast cancer is a common malignant disease, which may be caused by a number of genes deregulated by genomic or epigenomic events. Deregulated WNT/beta-catenin signaling with accumulation of beta-catenin is common in breast tumors, but mutations in WNT signaling pathway components have been rare. An aberrantly spliced internally truncated LRP5 receptor (LRP5Delta666-809, LRP5Delta) was shown recently to be resistant to DKK1 inhibition, and was required for beta-catenin accumulation in hyperparathyroid tumors and parathyroid tumor growth.
METHODOLOGY/PRINCIPAL FINDINGS: Here we show, by reverse transcription PCR and Western blot analysis, that LRP5Delta is frequently expressed in breast tumors of different cancer stage (58-100%), including carcinoma in situ and metastatic carcinoma. LRP5Delta was required in MCF7 breast cancer cells for the non-phosphorylated active beta-catenin level, transcription activity of beta-catenin, cell growth in vitro, and breast tumor growth in a xenograft SCID mouse model. WNT3 ligand, but not WNT1 and WNT3A augmented the endogenous beta-catenin activity of MCF7 cells in a DKK1-insensitive manner. Furthermore, an anti-LRP5 antibody attenuated beta-catenin activity, inhibited cell growth, and induced apoptosis in LRP5Delta-positive MCF7 and T-47D breast cancer cells, but not in control cells.
CONCLUSIONS/SIGNIFICANCE: Our results suggest that the LRP5Delta receptor is strongly implicated in mammary gland tumorigenesis and that its aberrant expression present an early event during disease progression. LRP5 antibody therapy may have a significant role in the treatment of breast cancer.

Cao H, Xu W, Qian H, et al.
Mesenchymal stem cell-like cells derived from human gastric cancer tissues.
Cancer Lett. 2009; 274(1):61-71 [PubMed] Related Publications
Mesenchymal stem cells (MSCs) have been identified in and isolated from numerous human tissues. The characteristics of mesenchymal stem cells, including their plasticity, the secretion of cytokines, and their low immunogenicity, contribute to their therapeutic potential. It has recently been reported that MSCs are also involved in tumorigenesis and its prognosis. Here, we present the first report of MSC-like cells isolated from human gastric cancer tissues. In our study, gastric cancer-derived MSC-like cells (hGC-MSCs) were isolated from 13 out of 20 cancer tissue samples. Their characteristics, including their morphology, surface antigens, specific gene expression, and differentiation potential, were similar to those of MSCs derived from human bone marrow (hBM-MSCs) but different from gastric cancer cells. The existence of MSC-like cells in gastric cancer tissues suggests that they may be potential targets for cancer therapy and provides an experimental foundation for investigating their role in the initiation and progression of gastric cancers.

Streeten EA, McBride D, Puffenberger E, et al.
Osteoporosis-pseudoglioma syndrome: description of 9 new cases and beneficial response to bisphosphonates.
Bone. 2008; 43(3):584-90 [PubMed] Free Access to Full Article Related Publications
Osteoporosis-pseudoglioma syndrome (OPPG) is a rare autosomal recessive disorder of severe juvenile osteoporosis and congenital blindness, due to mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene. Approximately fifty cases of OPPG have been reported. We report 9 new cases of OPPG, in three related nuclear families of Conservative Mennonites in Pennsylvania. All 9 children with OPPG were blind and had osteoporosis. Four of six parents had low bone mineral density (BMD) or osteoporosis; 2 were normal. Sequence analysis from genomic DNA revealed homozygosity for a nonsense mutation of exon 6 of LRP5 (W425X) in four OPPG cases tested in families A and C. In family B, OPPG cases were compound heterozygotes for the exon 6 W425X LRP5 mutation and a second exon 6 mutation (T409A); bone phenotype was milder than in family A. Neither of these mutations was present in an unrelated normal. The four treated OPPG patients all responded to bisphosphonates (duration 1.5-6.5 years) with improvement in Z-scores. One patient had a negligible response to teriparatide. In summary, we report 9 new cases of OPPG due to two novel LRP5 mutations, note a milder bone phenotype but similar ocular phenotype in LRP5 W425X/T409A compound heterozygotes than in W425X homozygotes and describe positive response to bisphosphonate treatment in four cases.

Guo Y, Xie J, Rubin E, et al.
Frzb, a secreted Wnt antagonist, decreases growth and invasiveness of fibrosarcoma cells associated with inhibition of Met signaling.
Cancer Res. 2008; 68(9):3350-60 [PubMed] Free Access to Full Article Related Publications
Soft tissue sarcomas (STS) have a strong propensity for aggressive growth and metastasis. We showed that the secreted Wnt antagonist Frzb exhibited potent antitumor activity against prostate cancer, an epithelial type of malignancy. In this study, we further showed the antitumor efficacy of Frzb in STS, a mesenchymal group of cancer. Frzb transfection of HT1080 (fibrosarcoma) and SW872 (liposarcoma) cell lines and their conditioned media resulted in a significant reduction in cellular invasion, motility, and colony formation in soft agar compared with vector control-transfected cells. In a xenograft mouse model, Frzb dramatically suppressed tumor growth of HT1080 cells in nude mice. In a tail-vein injection metastatic model, Frzb-transfected HT1080 cells formed fewer and smaller lung nodules than vector control cells. In addition, we identified new mechanisms for Frzb antitumor activities. Frzb reduced c-Met expression and inhibited Met-mediated signaling, associated with up-regulation of epithelial markers (i.e., keratins 8 and 18) and down-regulation of mesenchymal markers (i.e., vimentin, N-cadherin, fibronectin, Slug, and Twist). Similar to Frzb, silencing of c-Met by short hairpin RNA or using a dominant-negative LRP5 receptor also suppressed Met signaling, leading to reduced cellular motility, invasion, and in vivo tumor growth. Given recent studies indicating an important role of c-Met in sarcoma development and progression, our data showed that Frzb expression was significantly inversely correlated with Met expression in both STS cell lines and tissues. These results suggested the usefulness of Frzb in modulating Met signaling as a new treatment strategy for STS.

French D, Hamilton LH, Mattano LA, et al.
A PAI-1 (SERPINE1) polymorphism predicts osteonecrosis in children with acute lymphoblastic leukemia: a report from the Children's Oncology Group.
Blood. 2008; 111(9):4496-9 [PubMed] Free Access to Full Article Related Publications
As glucocorticoid use increased in acute lymphoblastic leukemia, osteonecrosis became an increasingly frequent complication. Besides increased age, host risk factors are poorly defined. We tested whether 12 polymorphisms were associated with osteonecrosis among patients 10 years and older treated on the CCG1882 protocol. Candidate genes (TYMS, MTHFR, ABCB1, BGLAP, ACP5, LRP5, ESR1, PAI-1, VDR, PTH, and PTHR) were chosen based on putative mechanisms underlying osteonecrosis risk. All children received dexamethasone, with doses varying by treatment arm. A PAI-1 polymorphism (rs6092) was associated with risk of osteonecrosis in univariate (P = .002; odds ratio = 2.79) and multivariate (P = .002; odds ratio = 2.89) analyses (adjusting for gender, age, and treatment arm). Overall, 21 of 78 (26.9%) children with PAI-1 GA/AA genotypes, versus 25 of 214 (11.7%) children with GG genotype, developed osteonecrosis. PAI-1 polymorphisms and PAI-1 serum levels have previously been associated with thrombosis. We conclude that PAI-1 genetic variation may contribute to risk of osteonecrosis.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. LRP5, Cancer Genetics Web: Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 27 February, 2015     Cancer Genetics Web, Established 1999