IGFBP3

Gene Summary

Gene:IGFBP3; insulin-like growth factor binding protein 3
Aliases: IBP3, BP-53
Location:7p12.3
Summary:This gene is a member of the insulin-like growth factor binding protein (IGFBP) family and encodes a protein with an IGFBP domain and a thyroglobulin type-I domain. The protein forms a ternary complex with insulin-like growth factor acid-labile subunit (IGFALS) and either insulin-like growth factor (IGF) I or II. In this form, it circulates in the plasma, prolonging the half-life of IGFs and altering their interaction with cell surface receptors. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:insulin-like growth factor-binding protein 3
HPRD
Source:NCBIAccessed: 27 February, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 28 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.

Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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: IGFBP3 (cancer-related)

Nurwidya F, Takahashi F, Kobayashi I, et al.
Treatment with insulin-like growth factor 1 receptor inhibitor reverses hypoxia-induced epithelial-mesenchymal transition in non-small cell lung cancer.
Biochem Biophys Res Commun. 2014; 455(3-4):332-8 [PubMed] Related Publications
Insulin-like growth factor 1 receptor (IGF1R) is expressed in many types of solid tumors including non-small cell lung cancer (NSCLC), and enhanced activation of IGF1R is thought to reflect cancer progression. Epithelial-mesenchymal transition (EMT) has been established as one of the mechanisms responsible for cancer progression and metastasis, and microenvironment conditions, such as hypoxia, have been shown to induce EMT. The purposes of this study were to address the role of IGF1R activation in hypoxia-induced EMT in NSCLC and to determine whether inhibition of IGF1R might reverse hypoxia-induced EMT. Human NSCLC cell lines A549 and HCC2935 were exposed to hypoxia to investigate the expression of EMT-related genes and phenotypes. Gene expression analysis was performed by quantitative real-time PCR and cell phenotypes were studied by morphology assessment, scratch wound assay, and immunofluorescence. Hypoxia-exposed cells exhibited a spindle-shaped morphology with increased cell motility reminiscent of EMT, and demonstrated the loss of E-cadherin and increased expression of fibronectin and vimentin. Hypoxia also led to increased expression of IGF1, IGF binding protein-3 (IGFBP3), and IGF1R, but not transforming growth factor β1 (TGFβ1). Inhibition of hypoxia-inducible factor 1α (HIF1α) with YC-1 abrogated activation of IGF1R, and reduced IGF1 and IGFBP3 expression in hypoxic cells. Furthermore, inhibition of IGF1R using AEW541 in hypoxic condition restored E-cadherin expression, and reduced expression of fibronectin and vimentin. Finally, IGF1 stimulation of normoxic cells induced EMT. Our findings indicated that hypoxia induced EMT in NSCLC cells through activation of IGF1R, and that IGF1R inhibition reversed these phenomena. These results suggest a potential role for targeting IGF1R in the prevention of hypoxia-induced cancer progression and metastasis mediated by EMT.

Yang CH, Yue J, Pfeffer SR, et al.
MicroRNA-21 promotes glioblastoma tumorigenesis by down-regulating insulin-like growth factor-binding protein-3 (IGFBP3).
J Biol Chem. 2014; 289(36):25079-87 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
Despite advances in surgery, imaging, chemotherapy, and radiation, patients with glioblastoma multiforme (GBM), the most common histological subtype of glioma, have an especially dismal prognosis; >70% of GBM patients die within 2 years of diagnosis. In many human cancers, the microRNA miR-21 is overexpressed, and accumulating evidence indicates that it functions as an oncogene. Here, we report that miR-21 is overexpressed in human GBM cell lines and tumor tissue. Moreover, miR-21 expression in GBM patient samples is inversely correlated with patient survival. Knockdown of miR-21 in GBM cells inhibited cell proliferation in vitro and markedly inhibited tumor formation in vivo. A number of known miR-21 targets have been identified previously. By microarray analysis, we identified and validated insulin-like growth factor (IGF)-binding protein-3 (IGFBP3) as a novel miR-21 target gene. Overexpression of IGFBP3 in glioma cells inhibited cell proliferation in vitro and inhibited tumor formation of glioma xenografts in vivo. The critical role that IGFBP3 plays in miR-21-mediated actions was demonstrated by a rescue experiment, in which IGFBP3 knockdown in miR-21KD glioblastoma cells restored tumorigenesis. Examination of tumors from GBM patients showed that there was an inverse relationship between IGFBP3 and miR-21 expression and that increased IGFBP3 expression correlated with better patient survival. Our results identify IGFBP3 as a novel miR-21 target gene in glioblastoma and suggest that the oncogenic miRNA miR-21 down-regulates the expression of IGFBP3, which acts as a tumor suppressor in human glioblastoma.

Kido T, Lo RC, Li Y, et al.
The potential contributions of a Y-located protooncogene and its X homologue in sexual dimorphisms in hepatocellular carcinoma.
Hum Pathol. 2014; 45(9):1847-58 [PubMed] Related Publications
There is a significant sex disparity favoring males among hepatocellular carcinoma (HCC) patients. Although various risk factors have been identified, the exact etiology of such sexual dimorphism(s) in HCC is uncertain. Previous studies showed that overexpression of the Y-located protooncogene, testis-specific protein Y encoded (TSPY), promotes cell proliferation and oncogenesis whereas its X-located homologue, TSPYhomologue X (TSPX), retards cell cycle and oncogenic progression. Furthermore, TSPX promotes proteasomal degradation of hepatitis B virus-encoded X oncoprotein and hence could serve as a tumor suppressor in virus-associated HCC. Using immunohistochemistry and reverse-transcription polymerase chain reaction analysis, we had examined the expression of TSPY and TSPX with reference to other established biomarkers in HCC and related liver cancers. Our results demonstrated that 55 (19.2%) of 287 male cases were TSPY positive in immunohistochemistry of tissue arrays, and 15 (46.9%) of 32 male cases were TSPY positive in reverse-transcription polymerase chain reaction analysis of clinical samples. TSPY expression was closely associated with the expression of HCC biomarkers, such as glypican 3. In contrast, TSPX expression was down-regulated in 54.5% of total tumor/nontumorous paired samples (18/33) and negatively associated with those of TSPY, glypican 3, and forkhead box M1 (FOXM1) and was positively associated with that of a tumor suppressor, insulin-like growth factor binding protein 3. The present findings support the hypothesis that the oncogenic events leading to an ectopic activation of the Y-located protooncogene TSPY and/or inactivating mutation/epigenetic silencing of the X-located tumor suppressor gene TSPX could collectively contribute to the sexual dimorphism(s) in HCC and related liver cancers in male-biased manners.

Shahmoon S, Rubinfeld H, Wolf I, et al.
The aging suppressor klotho: a potential regulator of growth hormone secretion.
Am J Physiol Endocrinol Metab. 2014; 307(3):E326-34 [PubMed] Related Publications
Klotho is a transmembranal protein highly expressed in the kidneys, choroid plexus, and anterior pituitary. Klotho can also be cleaved and shed and acts as a circulating hormone. Klotho-deficient mice (kl/kl mice) develop a phenotype resembling early aging. Several lines of evidence suggest a role for klotho in the regulation of growth hormone (GH) secretion. The kl/kl mice are smaller compared with their wild-type counterparts, and their somatotropes show reduced numbers of secretory granules. Moreover, klotho is a potent inhibitor of the IGF-I pathway, a negative regulator of GH secretion. Therefore, we hypothesized that klotho may enhance GH secretion. The effect of klotho on GH secretion was examined in GH3 rat somatotrophs, cultured rat pituitaries, and cultured human GH-secreting adenomas. In all three models, klotho treatment increased GH secretion. Prolonged treatment of mice with intraperitoneal klotho injections increased mRNA levels of IGF-I and IGF-I-binding protein-3 mRNA in the liver, reflecting increased serum GH levels. In accord with its ability to inhibit the IGF-I pathway, klotho partially restored the inhibitory effect of IGF-I on GH secretion. Klotho is known to be a positive regulator of basic bFGF signaling. We studied rat pituitaries and human adenoma cultures and noted that bFGF increased GH secretion and stimulated ERK1/2 phosphorylation. Both effects were augmented following treatment with klotho. Taken together, our data indicate for the first time that klotho is a positive regulator of GH secretion and suggest the IGF-I and bFGF pathways as potential mediators of this effect.

Tu M, Liu X, Han B, et al.
Vasohibin‑2 promotes proliferation in human breast cancer cells via upregulation of fibroblast growth factor‑2 and growth/differentiation factor‑15 expression.
Mol Med Rep. 2014; 10(2):663-9 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
Vasohibin‑2 (VASH2) is an angiogenic factor, and has been previously reported to be a cancer‑related gene, with cytoplasmic and karyotypic forms. In the current study VASH2 expression in human breast cancer tissue and adjacent non‑cancerous tissue was investigated with immunohistochemistry. MCF‑7 and BT474 human breast cancer cells were transfected with lentiviral constructs to generate in vitro VASH2 overexpression and knockdown models. In addition, BALB/cA nude mice were inoculated subcutaneously with transfected cells to generate in vivo models of VASH2 overexpression and knockdown. The effect of VASH2 on cell proliferation was investigated using a bromodeoxyuridine assay in vitro and immunohistochemistry of Ki67 in xenograft tumors. Growth factors were investigated using a human growth factor array, and certain factors were further confirmed by an immunoblot. The results indicated that the expression level of cytoplasmic VASH2 was higher in breast cancer tissues with a Ki67 (a proliferation marker) level of ≥14%, compared with tissues with a Ki67 level of <14%. VASH2 induced proliferation in vitro and in vivo. Four growth factors activated by VASH2 were identified as follows: Fibroblast growth factor 2 (FGF2), growth/differentiation factor‑15 (GDF15), insulin‑like growth factor‑binding protein (IGFBP)3 and IGFBP6. FGF2 and GDF15 may contribute to VASH2‑induced proliferation. The current study identified a novel role for VASH2 in human breast cancer, and this knowledge suggests that VASH2 may be a novel target in breast cancer treatment.

Kang S, Zhao Y, Hu K, et al.
miR-124 exhibits antiproliferative and antiaggressive effects on prostate cancer cells through PACE4 pathway.
Prostate. 2014; 74(11):1095-106 [PubMed] Related Publications
INTRODUCTION: PACE4 plays an important role in prostate cancer (PCa) proliferation and aggression, which might provide a useful target against prostate cancer. In this study, we had strived to find some key miRNAs to decrease malignancy and invasiveness of PCa through regulating PACE4 expression.
METHODS: Clinically pathological analysis of immunohistochemistry/in situ hybridization was carried out to detect the relationship between PACE4 expression/miRNAs and the malignancy of prostate mass. Prostate cell lines (DU145, C4-2, and BPH-1) were cultured for growth curve, immunocytochemistry analysis, colony formation, Matrigel invasion, and transcriptional/translational expression assay of PACE4-related signaling molecules for confirming the relationship. MiRNAs targeting PACE4 were predicted, validated and further-corroborated using bio-software, real-time PCR, luciferase reporter assay and transfection of miRNA mimics and inhibitor.
RESULTS: It was suggested that PACE4 might reflect the pathological malignancy of prostate lesion from pathology analysis. Moreover, DU145 cells, the highest PACE4-level and related TF expression indicated of the strongest malignancy and invasiveness. It was significantly found that miR-124 was presented with the biggest odd to target PACE4-3'UTR, the capability of decreasing PACE expression and slowing down cell growth and cell invasion.
CONCLUSIONS: It was clear that PACE4 level was closely associated with malignancy and invasiveness of PCa in vivo or in vitro MiR-124, played a crucial role inhibiting PACE4 transcription thus exhibiting obvious effects of antiproliferation and antiaggression of PCa.

Thota B, Arimappamagan A, Kandavel T, et al.
STAT-1 expression is regulated by IGFBP-3 in malignant glioma cells and is a strong predictor of poor survival in patients with glioblastoma.
J Neurosurg. 2014; 121(2):374-83 [PubMed] Related Publications
OBJECT: Insulin-like growth factor binding proteins (IGFBPs) have been implicated in the pathogenesis of glioma. In a previous study the authors demonstrated that IGFBP-3 is a novel glioblastoma biomarker associated with poor survival. Since signal transducer and activator of transcription 1 (STAT-1) has been shown to be regulated by IGFBP-3 during chondrogenesis and is a prosurvival and radioresistant molecule in different tumors, the aim in the present study was to explore the functional significance of IGFBP-3 in malignant glioma cells, to determine if STAT-1 is indeed regulated by IGFBP-3, and to study the potential of STAT-1 as a biomarker in glioblastoma.
METHODS: The functional significance of IGFBP-3 was investigated using the short hairpin (sh)RNA gene knockdown approach on U251MG cells. STAT-1 regulation by IGFBP-3 was tested on U251MG and U87MG cells by shRNA gene knockdown and exogenous treatment with recombinant IGFBP-3 protein. Subsequently, the expression of STAT-1 was analyzed with real-time reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) in glioblastoma and control brain tissues. Survival analyses were done on a uniformly treated prospective cohort of adults with newly diagnosed glioblastoma (136 patients) using Kaplan-Meier and Cox regression models.
RESULTS: IGFBP-3 knockdown significantly impaired proliferation, motility, migration, and invasive capacity of U251MG cells in vitro (p < 0.005). Exogenous overexpression of IGFBP-3 in U251MG and U87MG cells demonstrated STAT-1 regulation. The mean transcript levels (by real-time RT-PCR) and the mean labeling index of STAT-1 (by IHC) were significantly higher in glioblastoma than in control brain tissues (p = 0.0239 and p < 0.001, respectively). Multivariate survival analysis revealed that STAT-1 protein expression (HR 1.015, p = 0.033, 95% CI 1.001-1.029) along with patient age (HR 1.025, p = 0.005, 95% CI 1.008-1.042) were significant predictors of shorter survival in patients with glioblastoma.
CONCLUSIONS: IGFBP-3 influences tumor cell proliferation, migration, and invasion and regulates STAT-1 expression in malignant glioma cells. STAT-1 is overexpressed in human glioblastoma tissues and emerges as a novel prognostic biomarker.

Cao Y, Lindström S, Schumacher F, et al.
Insulin-like growth factor pathway genetic polymorphisms, circulating IGF1 and IGFBP3, and prostate cancer survival.
J Natl Cancer Inst. 2014; 106(6):dju085 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
BACKGROUND: The insulin-like growth factor (IGF) signaling pathway has been implicated in prostate cancer (PCa) initiation, but its role in progression remains unknown.
METHODS: Among 5887 PCa patients (704 PCa deaths) of European ancestry from seven cohorts in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium, we conducted Cox kernel machine pathway analysis to evaluate whether 530 tagging single nucleotide polymorphisms (SNPs) in 26 IGF pathway-related genes were collectively associated with PCa mortality. We also conducted SNP-specific analysis using stratified Cox models adjusting for multiple testing. In 2424 patients (313 PCa deaths), we evaluated the association of prediagnostic circulating IGF1 and IGFBP3 levels and PCa mortality. All statistical tests were two-sided.
RESULTS: The IGF signaling pathway was associated with PCa mortality (P = .03), and IGF2-AS and SSTR2 were the main contributors (both P = .04). In SNP-specific analysis, 36 SNPs were associated with PCa mortality with P trend less than .05, but only three SNPs in the IGF2-AS remained statistically significant after gene-based corrections. Two were in linkage disequilibrium (r 2 = 1 for rs1004446 and rs3741211), whereas the third, rs4366464, was independent (r 2 = 0.03). The hazard ratios (HRs) per each additional risk allele were 1.19 (95% confidence interval [CI] = 1.06 to 1.34; P trend = .003) for rs3741211 and 1.44 (95% CI = 1.20 to 1.73; P trend < .001) for rs4366464. rs4366464 remained statistically significant after correction for all SNPs (P trend.corr = .04). Prediagnostic IGF1 (HRhighest vs lowest quartile = 0.71; 95% CI = 0.48 to 1.04) and IGFBP3 (HR = 0.93; 95% CI = 0.65 to 1.34) levels were not associated with PCa mortality.
CONCLUSIONS: The IGF signaling pathway, primarily IGF2-AS and SSTR2 genes, may be important in PCa survival.

Kim E, Jeon WB, Kim S, Lee SK
Decrease of reactive oxygen species-related biomarkers in the tissue-mimic 3D spheroid culture of human lung cells exposed to zinc oxide nanoparticles.
J Nanosci Nanotechnol. 2014; 14(5):3356-65 [PubMed] Related Publications
Common 2-dimensional (2D) cell cultures do not adequately represent cell-cell and cell-matrix signaling and substantially different diffusion/transport pathways. To obtain tissue-mimic information on nanoparticle toxicity from in vitro cell tests, we used a 3-dimensional (3D) culture of human lung cells (A549) prepared with elastin-like peptides modified with an arginine-glycine-aspartate motif. The 3D cells showed different cellular phenotypes, gene expression profiles, and functionalities compared to the 2D cultured cells. In gene array analysis, 3D cells displayed the induced extracellular matrix (ECM)-related biological functions such as cell-to-cell signaling and interaction, cellular function and maintenance, connective tissue development and function, molecular transport, and tissue morphology. Additionally, the expression of ECM-related molecules, such as laminin, fibronectin, and insulin-like growth factor binding protein 3 (IGFBP3), was simultaneously induced at both mRNA and protein levels. When 0.08-50 microg/ml zinc oxide nanoparticles (ZnO-NPs) were administered to 2D and 3D cells, the cell proliferation was not significantly changed. The level of molecular markers for oxidative stress, such as superoxide dismutase (SOD), Bcl-2, ATP synthase, and Complex IV (cytochrome C oxidase), was significantly reduced in 2D culture when exposed to 10 microg/ml ZnO-NPs, but no significant decrease was detected in 3D culture when exposed to the same concentration of ZnO-NPs. In conclusion, the tissue-mimic phenotype and functionality of 3D cells could be achieved through the elevated expression of ECM components. The 3D cells were expected to help to better predict the nanotoxicity of ZnO-NPs at tissue-level by increased cell-cell and cell-ECM adhesion and signaling. The tissue-mimic morphology would also be useful to simulate the diffusion/transport of the nanoparticles in vitro.

Long Q, Xu J, Osunkoya AO, et al.
Global transcriptome analysis of formalin-fixed prostate cancer specimens identifies biomarkers of disease recurrence.
Cancer Res. 2014; 74(12):3228-37 [PubMed] Article available free on PMC after 15/06/2015 Related Publications
Prostate cancer remains the second leading cause of cancer death in American men and there is an unmet need for biomarkers to identify patients with aggressive disease. In an effort to identify biomarkers of recurrence, we performed global RNA sequencing on 106 formalin-fixed, paraffin-embedded prostatectomy samples from 100 patients at three independent sites, defining a 24-gene signature panel. The 24 genes in this panel function in cell-cycle progression, angiogenesis, hypoxia, apoptosis, PI3K signaling, steroid metabolism, translation, chromatin modification, and transcription. Sixteen genes have been associated with cancer, with five specifically associated with prostate cancer (BTG2, IGFBP3, SIRT1, MXI1, and FDPS). Validation was performed on an independent publicly available dataset of 140 patients, where the new signature panel outperformed markers published previously in terms of predicting biochemical recurrence. Our work also identified differences in gene expression between Gleason pattern 4 + 3 and 3 + 4 tumors, including several genes involved in the epithelial-to-mesenchymal transition and developmental pathways. Overall, this study defines a novel biomarker panel that has the potential to improve the clinical management of prostate cancer.

Qian J, Zhou H, Chen J, et al.
Genetic polymorphisms in IGF-I and IGFBP-3 are associated with prostate cancer in the Chinese population.
PLoS One. 2014; 9(2):e85609 [PubMed] Article available free on PMC after 15/06/2015 Related Publications
Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) are members of the insulin-like growth factor (IGF) family that play important roles in carcinogenesis. We hypothesized that the functional polymorphisms in IGF-I and IGFBP-3 may be associated with the risk of prostate cancer (PCa) in the Chinese population. This hospital-based case-control study included 664 PCa patients and 702 cancer-free controls. Nine SNPs in IGF-I and IGFBP-3 were genotyped using the TaqMan assay. The genetic associations between the pathogenesis and progression of PCa were assessed by logistic regression. We found that the genotype and allele frequency distribution of rs6218, rs35767 and rs5742612 were significantly different when comparing PCa cases to controls (P  = 0.005, 0.005 and 0.020, respectively). In the combined analysis, individuals with 2-6 risk alleles had an elevated risk of PCa compared to those with 0-1 risk alleles. We also found that the association between the combined risk alleles and the risk of PCa appeared stronger in the following subgroups: individuals older than 71 years of age (OR  = 1.41, 95%CI  = 1.05-1.91, P  = 0.020), nonsmokers (OR  = 1.68, 95%CI  = 1.21-2.32, P  = 0.002), nondrinkers (OR  = 1.32, 95%CI  = 1.02-1.61, P  = 0.002), and those with a negative family history of PCa (OR  = 1.28, 95%CI  = 1.02-1.71, P  = 0.022). Our results indicate that the three SNPs (rs6218, rs35767 and rs5742612) and the joint genotypes with 2-6 risk alleles, may contribute to the susceptibility to PCa, but not the progression, in the Chinese population.

Jafaar ZM, Litchfield LM, Ivanova MM, et al.
β-D-glucan inhibits endocrine-resistant breast cancer cell proliferation and alters gene expression.
Int J Oncol. 2014; 44(4):1365-75 [PubMed] Article available free on PMC after 15/06/2015 Related Publications
Endocrine therapies have been successfully used for breast cancer patients with estrogen receptor α (ERα) positive tumors, but ~40% of patients relapse due to endocrine resistance. β-glucans are components of plant cell walls that have immunomodulatory and anticancer activity. The objective of this study was to examine the activity of β-D-glucan, purified from barley, in endocrine-sensitive MCF-7 versus endocrine-resistant LCC9 and LY2 breast cancer cells. β-D-glucan dissolved in DMSO but not water inhibited MCF-7 cell proliferation in a concentration-dependent manner as measured by BrdU incorporation with an IC₅₀ of ~164 ± 12 µg/ml. β-D-glucan dissolved in DMSO inhibited tamoxifen/endocrine-resistant LCC9 and LY2 cell proliferation with IC₅₀ values of 4.6 ± 0.3 and 24.2 ± 1.4 µg/ml, respectively. MCF-10A normal breast epithelial cells showed a higher IC₅₀ ~464 µg/ml and the proliferation of MDA-MB-231 triple negative breast cancer cells was not inhibited by β-D-glucan. Concentration-dependent increases in the BAX/BCL2 ratio and cell death with β-D-glucan were observed in MCF-7 and LCC9 cells. PCR array analysis revealed changes in gene expression in response to 24-h treatment with 10 or 50 µg/ml β-D-glucan that were different between MCF-7 and LCC9 cells as well as differences in basal gene expression between the two cell lines. Select results were confirmed by quantitative real-time PCR demonstrating that β-D-glucan increased RASSF1 expression in MCF-7 cells and IGFBP3, CTNNB1 and ERβ transcript expression in LCC9 cells. Our data indicate that β-D-glucan regulates breast cancer-relevant gene expression and may be useful for inhibiting endocrine-resistant breast cancer cell proliferation.

Zawadzka AM, Schilling B, Cusack MP, et al.
Phosphoprotein secretome of tumor cells as a source of candidates for breast cancer biomarkers in plasma.
Mol Cell Proteomics. 2014; 13(4):1034-49 [PubMed] Article available free on PMC after 15/06/2015 Related Publications
Breast cancer is a heterogeneous disease whose molecular diversity is not well reflected in clinical and pathological markers used for prognosis and treatment selection. As tumor cells secrete proteins into the extracellular environment, some of these proteins reach circulation and could become suitable biomarkers for improving diagnosis or monitoring response to treatment. As many signaling pathways and interaction networks are altered in cancerous tissues by protein phosphorylation, changes in the secretory phosphoproteome of cancer tissues could reflect both disease progression and subtype. To test this hypothesis, we compared the phosphopeptide-enriched fractions obtained from proteins secreted into conditioned media (CM) derived from five luminal and five basal type breast cancer cell lines using label-free quantitative mass spectrometry. Altogether over 5000 phosphosites derived from 1756 phosphoproteins were identified, several of which have the potential to qualify as phosphopeptide plasma biomarker candidates for the more aggressive basal and also the luminal-type breast cancers. The analysis of phosphopeptides from breast cancer patient plasma and controls allowed us to construct a discovery list of phosphosites under rigorous collection conditions, and second to qualify discovery candidates generated from the CM studies. Indeed, a set of basal-specific phosphorylation CM site candidates derived from IBP3, CD44, OPN, FSTL3, LAMB1, and STC2, and luminal-specific candidates derived from CYTC and IBP5 were selected and, based on their presence in plasma, quantified across all cell line CM samples using Skyline MS1 intensity data. Together, this approach allowed us to assemble a set of novel cancer subtype specific phosphopeptide candidates for subsequent biomarker verification and clinical validation.

Akker M, Güldiken S, Sipahi T, et al.
Investigation of insulin resistance gene polymorphisms in patients with differentiated thyroid cancer.
Mol Biol Rep. 2014; 41(5):3541-7 [PubMed] Related Publications
We aimed to investigate insulin receptor substrate-1 (IRS-1), insulin receptor substrate-2 (IRS-2), insulin-like growth factor binding protein-3 (IGFBP-3) genotypes, which are thought to be involved in the pathogenesis of many solid tumors and have thus far not been studied in patients with differentiated thyroid cancer (DTC). The study consisted of 93 patients diagnosed with DTC (79 females, 14 males) and 111 healthy control subjects (63 females, 48 males). The anthropometric measurements, lipid profiles, thyroid function tests and homeostatic model assessment (HOMA) as an indicator of insulin resistance (IR) of all patients were recorded. In addition IRS-1, IRS-2 and IGFBP-3 gene polymorphisms were determined by using polymerase chain reaction and restriction fragment length polymorphism. Hardy-Weinberg equilibrium was tested for each gene polymorphisms, and genetic effects were evaluated by the Chi Square test and multiple logistic regression. Homeostasis model assessment of insulin resistance (HOMA-IR), body mass index, waist circumference and serum total cholesterol levels were significantly higher in patients with DTC than in the control group. There was no difference between the two groups with respect to IRS-1, IRS-2 and IGFBP-3 gene polymorphisms. In addition, these gene polymorphisms were found to have no effect on lymph node metastases or tumor staging. While, obesity and increased HOMA-IR may be risk factors in DTC development, we suggest that IRS-1, IRS-2 and IGFBP-3 gene polymorphisms do not play an important role in pathogenesis of DTC.

Hensley PJ, Desiniotis A, Wang C, et al.
Novel pharmacologic targeting of tight junctions and focal adhesions in prostate cancer cells.
PLoS One. 2014; 9(1):e86238 [PubMed] Article available free on PMC after 15/06/2015 Related Publications
Cancer cell resistance to anoikis driven by aberrant signaling sustained by the tumor microenvironment confers high invasive potential and therapeutic resistance. We recently generated a novel lead quinazoline-based Doxazosin® derivative, DZ-50, which impairs tumor growth and metastasis via anoikis. Genome-wide analysis in the human prostate cancer cell line DU-145 identified primary downregulated targets of DZ-50, including genes involved in focal adhesion integrity (fibronectin, integrin-α6 and talin), tight junction formation (claudin-11) as well as insulin growth factor binding protein 3 (IGFBP-3) and the angiogenesis modulator thrombospondin 1 (TSP-1). Confocal microscopy demonstrated structural disruption of both focal adhesions and tight junctions by the downregulation of these gene targets, resulting in decreased cell survival, migration and adhesion to extracellular matrix (ECM) components in two androgen-independent human prostate cancer cell lines, PC-3 and DU-145. Stabilization of cell-ECM interactions by overexpression of talin-1 and/or exposing cells to a fibronectin-rich environment mitigated the effect of DZ-50. Loss of expression of the intracellular focal adhesion signaling effectors talin-1 and integrin linked kinase (ILK) sensitized human prostate cancer to anoikis. Our findings suggest that DZ-50 exerts its antitumor effect by targeting the key functional intercellular interactions, focal adhesions and tight junctions, supporting the therapeutic significance of this agent for the treatment of advanced prostate cancer.

Pan S, Chen R, Tamura Y, et al.
Quantitative glycoproteomics analysis reveals changes in N-glycosylation level associated with pancreatic ductal adenocarcinoma.
J Proteome Res. 2014; 13(3):1293-306 [PubMed] Article available free on PMC after 15/06/2015 Related Publications
Glycosylation plays an important role in epithelial cancers, including pancreatic ductal adenocarcinoma. However, little is known about the glycoproteome of the human pancreas or its alterations associated with pancreatic tumorigenesis. Using quantitative glycoproteomics approach, we investigated protein N-glycosylation in pancreatic tumor tissue in comparison with normal pancreas and chronic pancreatitis tissue. The study lead to the discovery of a roster of glycoproteins with aberrant N-glycosylation level associated with pancreatic cancer, including mucin-5AC (MUC5AC), carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), insulin-like growth factor binding protein (IGFBP3), and galectin-3-binding protein (LGALS3BP). Pathway analysis of cancer-associated aberrant glycoproteins revealed an emerging phenomenon that increased activity of N-glycosylation was implicated in several pancreatic cancer pathways, including TGF-β, TNF, NF-kappa-B, and TFEB-related lysosomal changes. In addition, the study provided evidence that specific N-glycosylation sites within certain individual proteins can have significantly altered glycosylation occupancy in pancreatic cancer, reflecting the complexity of the molecular mechanisms underlying cancer-associated glycosylation events.

Ge W, Li Y, Xiang H, Li H
Lack of association of IGFBP-3 gene polymorphisms with colorectal cancer: evidence from 17,380 subjects.
Mol Biol Rep. 2014; 41(4):2609-15 [PubMed] Related Publications
Published data on the association of IGFBP-3 gene polymorphisms with colorectal cancer (CRC) are inconclusive. We conducted a meta-analysis to derive a precise estimation of the association. A literature search that included PubMed, EMBASE, Elsevier Science Direct and China National Knowledge Infrastructure was conducted to identify studies up to October 15, 2013. Summary odds ratios (ORs) and 95 % confidence intervals (95 % CIs) for IGFBP-3 gene polymorphisms and CRC were calculated in a fixed effect model or a random effect model. We identified 10 separate studies including 7,000 cases and 10,380 controls using search. Meta-analysis was performed for two IGFBP-3 gene polymorphisms (rs2854744 and rs2854746). We found no association between IGFBP-3 gene rs2854744 polymorphism and CRC (P > 0.05). Similar result was observed between rs2854746 polymorphism and CRC (P > 0.05). This meta-analysis demonstrates that there is no association of IGFBP-3 gene rs2854744 and rs2854746 polymorphisms with CRC risk.

Gu J, Li M, Dong P, et al.
Role of polymorphisms of the IGF2 and IGFBP3 genes and risk of gastric carcinoma in China.
Chin Med J (Engl). 2014; 127(3):412-6 [PubMed] Related Publications
BACKGROUND: The insulin-like growth factor signaling pathway plays an important role in the modulation of cell growth and proliferation. The aim of this study was to investigate the role of polymorphisms of the insulin-like growth factor 2 (IGF2) and IGF-binding protein 3 (IGFBP3) genes, which encode key proteins of this pathway, as risk factors for gastric carcinoma (GC).
METHODS: A case-control study including 404 histologically confirmed GC patients and 424 healthy controls of the same ethnicity was conducted to retrospectively investigate the genetic polymorphisms of two genes, IGF2+820A>G (rs680) and IGFBP3 A-202C (rs2854744). Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using Logistic regression.
RESULTS: The IGF2 genetic variants examined contributed to GC risk individually (OR, 1.26; 95% CI, 1.08-1.46). The genotype frequencies of IGFBP3 A-202C were not significantly different between the cancer cases and controls (P > 0.05). Compared to the IGF2 AA genotype, carriers of one variant combined genotype were more pronounced among young subjects (<60 years), male subjects, never smokers, and those with a family history of cancer (OR = 1.36, 95% CI = 1.09-1.72, P < 0.05; OR = 1.61, 95% CI = 1.28-2.08, P < 0.05; OR = 1.46, 95% CI = 1.11-1.98, P < 0.05; OR = 1.53, 95% CI = 0.91-2.6, P < 0.05; respectively). Moreover, when the combined effects of the risk genotypes were investigated, significant associations were detected between highrisk genotypes in IGF2 and IGFBP3 (OR, 2.47; 95% CI, 1.75-3.49).
CONCLUSIONS: Our results suggest that polymorphic variants of the IGF2 genes modulate gastric carcinogenesis. Moreover, when the IGF2 and IGFBP3 variants are evaluated together, a greater effect on GC risk is observed.

Peng Z, Skoog L, Hellborg H, et al.
An expression signature at diagnosis to estimate prostate cancer patients' overall survival.
Prostate Cancer Prostatic Dis. 2014; 17(1):81-90 [PubMed] Article available free on PMC after 15/06/2015 Related Publications
BACKGROUND: This study aimed to identify biomarkers for estimating the overall and prostate cancer (PCa)-specific survival in PCa patients at diagnosis.
METHODS: To explore the importance of embryonic stem cell (ESC) gene signatures, we identified 641 ESC gene predictors (ESCGPs) using published microarray data sets. ESCGPs were selected in a stepwise manner, and were combined with reported genes. Selected genes were analyzed by multiplex quantitative polymerase chain reaction using prostate fine-needle aspiration samples taken at diagnosis from a Swedish cohort of 189 PCa patients diagnosed between 1986 and 2001. Of these patients, there was overall and PCa-specific survival data available for 97.9%, and 77.9% were primarily treated by hormone therapy only. Univariate and multivariate Cox proportional hazard ratios and Kaplan-Meier plots were used for the survival analysis, and a k-nearest neighbor (kNN) algorithm for estimating overall survival.
RESULTS: An expression signature of VGLL3, IGFBP3 and F3 was shown sufficient to categorize the patients into high-, intermediate- and low-risk subtypes. The median overall survival times of the subtypes were 3.23, 4.00 and 9.85 years, respectively. The difference corresponded to hazard ratios of 5.86 (95% confidence interval (CI): 2.91-11.78, P<0.001) for the high-risk subtype and 3.45 (95% CI: 1.79-6.66, P<0.001) for the intermediate-risk compared with the low-risk subtype. The kNN models that included the gene expression signature outperformed the one designed on clinical parameters alone.
CONCLUSIONS: The expression signature can potentially be used to estimate overall survival time. When validated in future studies, it could be integrated in the routine clinical diagnostic and prognostic procedure of PCa for an optimal treatment decision based on the estimated survival benefit.

Xue M, Fang Y, Sun G, et al.
IGFBP3, a transcriptional target of homeobox D10, is correlated with the prognosis of gastric cancer.
PLoS One. 2013; 8(12):e81423 [PubMed] Article available free on PMC after 15/06/2015 Related Publications
Homeobox D10 (HoxD10) plays important roles in the differentiation of embryonic cells and progression of breast cancer. Our previous report revealed that insulin-like growth factor binding protein-3 (IGFBP3) was regulated by HoxD10 in gastric cancer cells; however, the functional roles and underlying mechanisms of IGFBP3 in gastric cancer remain unclear. Here, we found that the expression of IGFBP3 were upregulated after ectopic expression of HoxD10 in gastric cancer cells. Chromatin immunoprecipitation assay showed that HoxD10 bound to three potential regions of IGFBP3 promoter. Exogenous HoxD10 significantly enhanced the activity of luciferase reporter containing these binding regions in gastric cancer cells. Further data showed that all of these binding sites had Hox binding element "TTAT". Immunohistochemical staining results revealed that IGFBP3 expression was significantly downregulated in 86 gastric adenocarcinomas tissues relative to their adjacent non-cancerous tissues (p<0.001). Moreover, IGFBP3 expression was significantly lower in gastric tumor with lymph node metastasis compared with that without lymph node metastasis (p=0.045). Patients with high expression level of IGFBP3 showed favorable 5 year overall survival (p=0.011). Knockdown of IGFBP3 accelerated gastric cancer cell migration and invasion and induced the expression of invasive factors including MMP14, uPA and uPAR. Thus, our data suggest that HoxD10-targeted gene IGFBP3 may suppress gastric cancer cell invasion and favors the survival of gastric cancer patients.

Martin JL, de Silva HC, Lin MZ, et al.
Inhibition of insulin-like growth factor-binding protein-3 signaling through sphingosine kinase-1 sensitizes triple-negative breast cancer cells to EGF receptor blockade.
Mol Cancer Ther. 2014; 13(2):316-28 [PubMed] Related Publications
The type I EGF receptor (EGFR or ErbB1) and insulin-like growth factor-binding protein-3 (IGFBP-3) are highly expressed in triple-negative breast cancer (TNBC), a particularly aggressive disease that cannot be treated with conventional therapies targeting the estrogen or progesterone receptors (ER and PR), or HER2. We have shown previously in normal breast epithelial cells that IGFBP-3 potentiates growth-stimulatory signaling transduced by EGFR, and this is mediated by the sphingosine kinase-1 (SphK1)/sphingosine 1-phosphate (S1P) system. In this study, we investigated whether cotargeting the EGFR and SphK1/S1P pathways in TNBC cells results in greater growth inhibition compared with blocking either alone, and might therefore have novel therapeutic potential in TNBC. In four TNBC cell lines, exogenous IGFBP-3 enhanced ligand-stimulated EGFR activation, associated with increased SphK1 localization to the plasma membrane. The effect of exogenous IGFBP-3 on EGFR activation was blocked by pharmacologic inhibition or siRNA-mediated silencing of SphK1, and silencing of endogenous IGFBP-3 also suppressed EGF-stimulated EGFR activation. Real-time analysis of cell proliferation revealed a combined effect of EGFR inhibition by gefitinib and SphK1 inhibition using SKi-II. Growth of MDA-MB-468 xenograft tumors in mice was significantly inhibited by SKi-II and gefitinib when used in combination, but not as single agents. We conclude that IGFBP-3 promotes growth of TNBC cells by increasing EGFR signaling, that this is mediated by SphK1, and that combined inhibition of EGFR and SphK1 has potential as an anticancer therapy in TNBC in which EGFR and IGFBP-3 expression is high.

Quan H, Tang H, Fang L, et al.
IGF1(CA)19 and IGFBP-3-202A/C gene polymorphism and cancer risk: a meta-analysis.
Cell Biochem Biophys. 2014; 69(1):169-78 [PubMed] Related Publications
Insulin-like growth factor 1 (IGF1)(CA)19 and insulin-like growth factor-binding protein-3 (IGFBP-3)-202A/C gene polymorphisms had been focused by many epidemiological studies recently, which were associated with common cancer risk including colorectal, breast, prostate, and lung cancer. However, the findings of epidemiological investigations are not coincident. We did a systematic review and meta-analysis of case-control studies, including studies nested in cohorts, of the association between IGF1(CA)19 and IGFBP-3-202A/C gene polymorphism and prostate, colorectal, premenopausal and postmenopausal breast cancer. We identified 17 eligible studies (24 datasets), which included 9,744 cases and 11,332 controls. The result displays that individuals carrying (CA)19 allele had a subtly decreased risk of all cancer sites [OR(95% CI) 0.92(0.87,0.97); 0.882(0.809,0.962); 0.902(0.849,0.958)] and postmenopausal breast cancer [OR(95% CI) 0.893(0.832,0.959); 0.834(0.719,0.968); 0.862(0.776,0.958)] in allele contrast model, CA19/CA19 vs. non-CA19/non-CA19 model, and recessive genetic model. In subgroup analysis according to ethnicities, (CA)19 repeat polymorphism had an increased risk of common cancers in Asian [OR (95% CI) of allele contrast model: 1.105(1.000,1.224); additive model: 1.103(0.844,1.441), 1.197(1.013,1.413); recessive model: 1.039(0.831,1.300); and dominant model: 1.191(1.030,1.376)]. On the other hand, IGFBP-3-202A/C gene polymorphism did not seem to be associated with all the cancer sites in any genetic model and ethnicity. In conclusion, the result of this meta-analysis indicates that the IGF1(CA)19 polymorphism is a candidate gene polymorphism for cancer susceptibility regardless of environmental factors, especially in Asian.

Huang YF, Cheng WF, Wu YP, et al.
Circulating IGF system and treatment outcome in epithelial ovarian cancer.
Endocr Relat Cancer. 2014; 21(2):217-29 [PubMed] Related Publications
Aggressive epithelial ovarian cancers (EOCs) frequently progress and become fatal, even when cytoreduction surgery plus platinum-based chemotherapy are performed. Thus, the early detection of high-risk subgroups is important in order to provide opportunities for better treatment outcomes, using alternative therapeutic strategies. This study aimed to explore the expression of circulating IGF system components and their relationship with treatment outcome in EOC. We included 228 patients with a median follow-up time of 44 months at two tertiary centers. There were 68 cancer deaths and 108 cases of cancer progression in the cohort. Preoperative serum levels of total IGF1, IGF2, IGF-binding protein 2 (IGFBP2), and IGFBP3 were analyzed using an ELISA and were then converted into an IGF1:IGFBP3 molar ratio. The risks of mortality and progression were estimated using Cox regression models in univariate and multivariate analyses. Our results showed that high IGF1, IGF2, and IGFBP3 levels were significantly associated with an early cancer stage, non-serous histology, and optimal cytoreduction. High IGFBP2 levels were associated with an advanced stage and serous histology. Overall and progression-free survival durations were significantly better among patients with high IGF1 (P=0.003 and P=0.001), IGF2 (P=0.003 and P=0.02), or IGFBP3 levels (P=0.02 and P=0.008). In multivariate analysis, serum IGFBP2 levels were significantly associated with increased risk of mortality (hazard ratio=1.84, 95% CI: 1.07-3.18, P=0.03), indicating that IGFBP2 could be used as an early predictor of EOC-related mortality. The combination of elevated IGFBP2 and reduced IGF1 levels at diagnosis could further facilitate the identification of a patient subgroup with the worst prognosis.

Prager AJ, Peng CR, Lita E, et al.
Urinary aHGF, IGFBP3 and OPN as diagnostic and prognostic biomarkers for prostate cancer.
Biomark Med. 2013; 7(6):831-41 [PubMed] Related Publications
AIM: Serum PSA screening for prostate cancer (PCa) is controversial. Here, we identify three urinary biomarkers - aHGF, IGFBP3 and OPN - for PCa screening and prognostication.
METHODS: Urinary aHGF, OPN and IGFBP3 from healthy men (n = 19) and men with localized (n = 65) and metastatic (n = 36) PCa were quantified via ELISA. Mann-Whitney nonparametric t-test and the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) analyses were used to analyze associations.
RESULTS: Mean aHGF and IGFBP3 levels were significantly elevated in PCa patients versus controls (p = 0.0006 and p = 0.0012, respectively), and the area under the curve of the receiver operating characteristic curve (indicator of diagnostic accuracy) for aHGF and IGFBP3 was 0.75 and 0.74, respectively. OPN levels were significantly higher in metastatic groups (p = 0.0060) versus localized and controls (area under the curve = 0.68).
CONCLUSION: Urinary aHGF and IGFBP3 exhibit the capacity for diagnostic discrimination for PCa, whereas OPN may indicate presence of metastatic disease.

Zhang T, Niu X, Liao L, et al.
The contributions of HIF-target genes to tumor growth in RCC.
PLoS One. 2013; 8(11):e80544 [PubMed] Article available free on PMC after 15/06/2015 Related Publications
Somatic mutations or loss of expression of tumor suppressor VHL happen in the vast majority of clear cell Renal Cell Carcinoma, and it's causal for kidney cancer development. Without VHL, constitutively active transcription factor HIF is strongly oncogenic and is essential for tumor growth. However, the contribution of individual HIF-responsive genes to tumor growth is not well understood. In this study we examined the contribution of important HIF-responsive genes such as VEGF, CCND1, ANGPTL4, EGLN3, ENO2, GLUT1 and IGFBP3 to tumor growth in a xenograft model using immune-compromised nude mice. We found that the suppression of VEGF or CCND1 impaired tumor growth, suggesting that they are tumor-promoting genes. We further discovered that the lack of ANGPTL4, EGLN3 or ENO2 expression did not change tumor growth. Surprisingly, depletion of GLUT1 or IGFBP3 significantly increased tumor growth, suggesting that they have tumor-inhibitory functions. Depletion of IGFBP3 did not lead to obvious activation of IGFIR. Unexpectedly, the depletion of IGFIR protein led to significant increase of IGFBP3 at both the protein and mRNA levels. Concomitantly, the tumor growth was greatly impaired, suggesting that IGFBP3 might suppress tumor growth in an IGFIR-independent manner. In summary, although the overall transcriptional activity of HIF is strongly tumor-promoting, the expression of each individual HIF-responsive gene could either enhance, reduce or do nothing to the kidney cancer tumor growth.

Ochs-Balcom HM, Vaughn CB, Nie J, et al.
Racial differences in the association of insulin-like growth factor pathway and colorectal adenoma risk.
Cancer Causes Control. 2014; 25(2):161-70 [PubMed] Article available free on PMC after 15/06/2015 Related Publications
PURPOSE: Insulin resistance is believed to play an important role in the link between energy imbalance and colon carcinogenesis. Emerging evidence suggests that there are substantial racial differences in genetic and anthropometric influences on insulin-like growth factors (IGFs); however, few studies have examined racial differences in the associations of IGFs and colorectal adenoma, precursor lesions of colon cancer.
METHODS: We examined the association of circulating levels of IGF-1, IGFBP-3 and IGFBP-1, and SNPs in the IGF-1 receptor (IGF1R), IGF-2 receptor (IGF2R), and insulin receptor genes with risk of adenomas in a sample of 410 incident adenoma cases and 1,070 controls from the Case Transdisciplinary Research on Energetics and Cancer (TREC) Colon Adenomas Study.
RESULTS: Caucasians have higher IGF-1 levels compared to African Americans; mean IGF-1 levels are 119.0 ng/ml (SD = 40.7) and 109.8 ng/ml (SD = 40.8), respectively, among cases (p = 0.02). Mean IGF-1 levels are also higher in Caucasian controls (122.9 ng/ml, SD = 41.2) versus African American controls (106.9, SD = 41.2), p = 0.001. We observed similar differences in IGFBP3 levels by race. Logistic regression models revealed a statistically significant association of IGF-1 with colorectal adenoma in African Americans only, with adjusted odds ratios (ORs) of 1.68 (95 % CI 1.06-2.68) and 1.68 (95 % CI 1.05-2.71), respectively, for the second and third tertiles as compared to the first tertile. One SNP (rs496601) in IGF1R was associated with adenomas in Caucasians only; the per allele adjusted OR is 0.73 (95 % CI 0.57-0.93). Similarly, one IGF2R SNP (rs3777404) was statistically significant in Caucasians; adjusted per allele OR is 1.53 (95 % CI 1.10-2.14).
CONCLUSION: Our results suggest racial differences in the associations of IGF pathway biomarkers and inherited genetic variance in the IGF pathway with risk of adenomas that warrant further study.

Karimi K, Mahmoudi T, Karimi N, et al.
Is there an association between variants in candidate insulin pathway genes IGF-I, IGFBP-3, INSR, and IRS2 and risk of colorectal cancer in the Iranian population?
Asian Pac J Cancer Prev. 2013; 14(9):5011-6 [PubMed] Related Publications
BACKGROUND: Several epidemiological studies have shown associations between colorectal cancer (CRC) risk and type 2 diabetes and obesity. Any effects would be expected to be mediated through the insulin pathway. Therefore it is possible that variants of genes encoding components of the insulin pathway play roles in CRC susceptibility. In this study, we hypothesized that polymorphisms in the genes involving the insulin pathway are associated with risk of CRC.
MATERIALS AND METHODS: The associations of four single nucleotide polymorphisms (SNPs) in IGF-I (rs6214), IGFBP-3 (rs3110697), INSR (rs1052371), and IRS2 (rs2289046) genes with the risk of CRC were evaluated using a case-control design with 167 CRC cases and 277 controls by the PCR-RFLP method.
RESULTS: Overall, we observed no significant difference in genotype and allele frequencies between the cases and controls for the IGF-I, IGFBP-3, INSR, IRS2 gene variants and CRC before or after adjusting for confounders (age, BMI, sex, and smoking status). However, we observed that the IRS2 (rs2289046) GG genotype compared with AA+AG genotypes has a protective effect for CRC in normal weight subjects (p=0.035, OR=0.259, 95%CI= 0.074-0.907).
CONCLUSIONS: These findings do not support plausible associations between polymorphic variations in IGF-I, IGFBP-3, INSR, IRS2 genes and risk of CRC. However, the evidence for a link between the IRS2 (rs2289046) variant and risk of CRC dependent on the BMI of the subjects, requires confirmation in subsequent studies with greater sample size.

Saldana SM, Lee HH, Lowery FJ, et al.
Inhibition of type I insulin-like growth factor receptor signaling attenuates the development of breast cancer brain metastasis.
PLoS One. 2013; 8(9):e73406 [PubMed] Article available free on PMC after 15/06/2015 Related Publications
Brain metastasis is a common cause of mortality in cancer patients, yet potential therapeutic targets remain largely unknown. The type I insulin-like growth factor receptor (IGF-IR) is known to play a role in the progression of breast cancer and is currently being investigated in the clinical setting for various types of cancer. The present study demonstrates that IGF-IR is constitutively autophosphorylated in brain-seeking breast cancer sublines. Knockdown of IGF-IR results in a decrease of phospho-AKT and phospho-p70s6k, as well as decreased migration and invasion of MDA-MB-231Br brain-seeking cells. In addition, transient ablation of IGFBP3, which is overexpressed in brain-seeking cells, blocks IGF-IR activation. Using an in vivo experimental brain metastasis model, we show that IGF-IR knockdown brain-seeking cells have reduced potential to establish brain metastases. Finally, we demonstrate that the malignancy of brain-seeking cells is attenuated by pharmacological inhibition with picropodophyllin, an IGF-IR-specific tyrosine kinase inhibitor. Together, our data suggest that the IGF-IR is an important mediator of brain metastasis and its ablation delays the onset of brain metastases in our model system.

Rinaldi S, Biessy C, Hernandez M, et al.
Circulating concentrations of insulin-like growth factor-I, insulin-like growth factor-binding protein-3, genetic polymorphisms and mammographic density in premenopausal Mexican women: results from the ESMaestras cohort.
Int J Cancer. 2014; 134(6):1436-44 [PubMed] Related Publications
The insulin-like growth factor (IGF) axis plays an essential role in the development of the mammary gland. High circulating levels of IGF-I and of its major binding protein IGFBP3 have been related with increased mammographic density in Caucasian premenopausal women. Some common single nucleotide polymorphisms (SNPs) in genes of the IGF pathway have also been suggested to play a role in mammographic density. We conducted a cross-sectional study nested within the large Mexican ESMaestras cohort to investigate the relation between circulating levels of IGF-I, IGFBP-3, the IGF-I/IGFBP-3 ratio, five common SNPs in the IGF-1, IGFBP-3 and IGF-1R genes and mammographic density in 593 premenopausal Mexican women. Mean age at mammogram was 43.1 (standard deviation, SD = 3.7) years, and average body mass index (BMI) at recruitment was 28.5 kg/m(2). Mean percent mammographic density was 36.5% (SD: 17.1), with mean dense tissue area of 48.3 (SD: 33.3) cm(2) . Mean IGF-I and IGFBP-3 concentrations were 15.33 (SD: 5.52) nmol/l and 114.96 (SD: 21.34) nmol/l, respectively. No significant associations were seen between percent density and biomarker concentrations, but women with higher IGF-I and IGF-I/IGFBP-3 concentrations had lower absolute dense (p(trend) = 0.03 and 0.09, respectively) and nondense tissue areas (p(trend) < 0.001 for both parameters). However, these associations were null after adjustment by BMI. SNPs in specific genes were associated with circulating levels of growth factors, but not with mammographic density features. These results do not support the hypothesis of a strong association between circulating levels of growth hormones and mammographic density in Mexican premenopausal women.

Zeitz MJ, Ay F, Heidmann JD, et al.
Genomic interaction profiles in breast cancer reveal altered chromatin architecture.
PLoS One. 2013; 8(9):e73974 [PubMed] Article available free on PMC after 15/06/2015 Related Publications
Gene transcription can be regulated by remote enhancer regions through chromosome looping either in cis or in trans. Cancer cells are characterized by wholesale changes in long-range gene interactions, but the role that these long-range interactions play in cancer progression and metastasis is not well understood. In this study, we used IGFBP3, a gene involved in breast cancer pathogenesis, as bait in a 4C-seq experiment comparing normal breast cells (HMEC) with two breast cancer cell lines (MCF7, an ER positive cell line, and MDA-MB-231, a triple negative cell line). The IGFBP3 long-range interaction profile was substantially altered in breast cancer. Many interactions seen in normal breast cells are lost and novel interactions appear in cancer lines. We found that in HMEC, the breast carcinoma amplified sequence gene family (BCAS) 1-4 were among the top 10 most significantly enriched regions of interaction with IGFBP3. 3D-FISH analysis indicated that the translocation-prone BCAS genes, which are located on chromosomes 1, 17, and 20, are in close physical proximity with IGFBP3 and each other in normal breast cells. We also found that epidermal growth factor receptor (EGFR), a gene implicated in tumorigenesis, interacts significantly with IGFBP3 and that this interaction may play a role in their regulation. Breakpoint analysis suggests that when an IGFBP3 interacting region undergoes a translocation an additional interaction detectable by 4C is gained. Overall, our data from multiple lines of evidence suggest an important role for long-range chromosomal interactions in the pathogenesis of cancer.

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