IGFBP4

Gene Summary

Gene:IGFBP4; insulin like growth factor binding protein 4
Aliases: BP-4, IBP4, IGFBP-4, HT29-IGFBP
Location:17q21.2
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 binds both insulin-like growth factors (IGFs) I and II and circulates in the plasma in both glycosylated and non-glycosylated forms. Binding of this protein prolongs the half-life of the IGFs and alters their interaction with cell surface receptors. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:insulin-like growth factor-binding protein 4
Source:NCBIAccessed: 11 March, 2017

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 (1992-2017)
Graph generated 11 March 2017 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.

  • Vitamin D Response Element
  • Estradiol
  • Receptors, Somatostatin
  • Infant
  • Gene Amplification
  • Valine
  • TGFB1
  • Transcription Factors
  • Gene Expression Regulation
  • Neoplastic Cell Transformation
  • Estrogen Antagonists
  • Cell Movement
  • Chromosome 17
  • RTPCR
  • Drug Resistance
  • Neoplasm Proteins
  • Cell Proliferation
  • Childhood Cancer
  • Cancer Gene Expression Regulation
  • Tamoxifen
  • Lung Cancer
  • Chromosome Mapping
  • Breast Cancer
  • X-Box Binding Protein 1
  • Phylogeny
  • Somatomedins
  • Tissue Array Analysis
  • Nucleic Acid Amplification Techniques
  • Oligonucleotide Array Sequence Analysis
  • Apoptosis
  • Gene Expression Profiling
  • Cluster Analysis
  • Estrogens
  • Insulin-Like Growth Factor Binding Protein 4
  • Cycloheximide
  • DNA-Binding Proteins
  • Signal Transduction
  • Small Cell Lung Cancer
  • beta Catenin
  • Estrogen Receptors
  • Messenger RNA
Tag cloud generated 11 March, 2017 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: IGFBP4 (cancer-related)

Minchenko DO, Kharkova AP, Halkin OV, et al.
Effect of hypoxia on the expression of genes encoding insulin-like growth factors and some related proteins in U87 glioma cells without IRE1 function.
Endocr Regul. 2016; 50(2):43-54 [PubMed] Related Publications
OBJECTIVE: The aim of the present study was to investigate the effect of hypoxia on the expression of genes encoding insulin-like growth factors (IGF1 and IGF2), their receptor (IGF1R), binding protein-4 (IGFBP4), and stanniocalcin 2 (STC2) in U87 glioma cells in relation to inhibition of endoplasmic reticulum stress signaling mediated by IRE1 (inositol requiring enzyme 1) for evaluation of their possible significance in the control of tumor growth.
METHODS: The expression of IGF1, IGF2, IGF1R, IGFBP4, and STC2 genes in U87 glioma cells transfected by empty vector pcDNA3.1 (control) and cells without IRE1 signaling enzyme function (transfected by dnIRE1) upon hypoxia was studied by qPCR.
RESULTS: The expression of IGF1 and IGF2 genes is down-regulated in glioma cells without IRE1 signaling enzyme function in comparison with the control cells. At the same time, the expression of IGF1R, IGFBP4, and STC2 genes was up-regulated in glioma cells upon inhibition of IRE1, with more significant changes for IGFBP4 and STC2 genes. We also showed that hypoxia does not change significantly the expression of IGF1, IGF2, and IGF1R genes but up-regulated IGFBP4 and STC2 genes expression in control glioma cells. Moreover, the inhibition of both enzymatic activities (kinase and endoribonuclease) of IRE1 in glioma cells does not change significantly the effect of hypoxia on the expression of IGF1, IGF1R, and IGFBP4 genes but introduces sensitivity of IGF2 gene to hypoxic condition. Thus, the expression of IGF2 gene is resistant to hypoxia only in control glioma cells and significantly down-regulated in cells without functional activity of IRE1 signaling enzyme, which is central mediator of the unfolded protein response and an important component of the tumor growth as well as metabolic diseases.
CONCLUSIONS: Results of this study demonstrate that the expression of IGF1 and IGF1R genes is resistant to hypoxic condition both in control U87 glioma cells and cells without IRE1 signaling enzyme function. However, hypoxia significantly up-regulates the expression of IGFBP4 gene independently on the inhibition of IRE1 enzyme. These data show that proteins encoded by these genes are resistant to hypoxia except IGFBP4 and participate in the regulation of metabolic and proliferative processes through IRE1 signaling.

Prithviraj P, Anaka M, McKeown SJ, et al.
Pregnancy associated plasma protein-A links pregnancy and melanoma progression by promoting cellular migration and invasion.
Oncotarget. 2015; 6(18):15953-65 [PubMed] Free Access to Full Article Related Publications
Melanoma is the most common cancer diagnosed in pregnant women and an aggressive course with poorer outcomes is commonly described during pregnancy or shortly after childbirth. The underlying mechanisms for this are not understood. Here, we report that melanoma migration, invasiveness and progression are promoted by Pregnancy-Associated Plasma Protein-A (PAPPA), a pregnancy-associated metalloproteinase produced by the placenta that increases the bioavailability of IGF1 by cleaving it from a circulating complex formed with IGFBP4. We show that PAPPA is widely expressed by metastatic melanoma tumors and is elevated in melanoma cells exhibiting mesenchymal, invasive and label-retaining phenotypes. Notably, inhibition of PAPPA significantly reduced invasion and migration of melanoma cells in vitro and in vivo within the embryonic chicken neural tube. PAPPA-enriched pregnancy serum treatment enhanced melanoma motility in vitro. Furthermore, we report that IGF1 can induce the phenotypic and functional effects of epithelial-to-mesenchymal transition (EMT) in melanoma cells. In this study, we establish a clear relationship between a pregnancy-associated protein PAPPA, melanoma and functional effects mediated through IGF1 that provides a plausible mechanism for accelerated melanoma progression during pregnancy. This opens the possibility of targeting the PAPPA/IGF1 axis therapeutically.

Meng G, Li Y, Lv Y, et al.
Preliminary screening of differentially expressed genes involved in methyl-CpG-binding protein 2 gene-mediated proliferation in human osteosarcoma cells.
Tumour Biol. 2015; 36(4):3009-15 [PubMed] Related Publications
Methyl-CpG-binding protein 2 (MeCP2) is essential in human brain development and has been linked to several cancer types and neuro-developmental disorders. This study aims to screen the MeCP2 related differentially expressed genes and discover the therapeutic targets for osteosarcoma. CCK8 assay was used to detect the proliferation and SaOS2 and U2OS cells. Apoptosis of cells was detected by flow cytometry analysis that monitored Annexin V-APC/7-DD binding and 7-ADD uptake simultaneously. Denaturing formaldehyde agarose gel electrophoresis was employed to examine the quality of total RNA 18S and 28S units. Gene chip technique was utilized to discover the differentially expressed genes correlated with MeCP2 gene. Differential gene screening criteria were used to screen the changed genes. The gene up-regulation or down-regulation more than 1.5 times was regarded as significant differential expression genes. The CCK8 results indicated that the cell proliferation of MeCP2 silencing cells (LV-MeCP2-RNAi) was significantly decreased compared to non-silenced cells (LV-MeCP2-RNAi-CN) (P < 0.05). MeCP2 silencing could also induce significant apoptosis compared to non-silenced cells (P < 0.05); 107 expression changed genes were screened from a total of 49,395 transcripts. Among the total 107 transcripts, 34 transcripts were up-regulated and 73 transcripts were down-regulated. There were five significant differentially expressed genes, including IGFBP4, HOXC8, LMO4, MDK, and CTGF, which correlated with the MeCP2 gene. The methylation frequency of CpG in IGFBP4 gene could achieve 55%. In conclusion, the differentially expressed IGFBP4, HOXC8, LMO4, MDK, and CTGF genes may be involved in MeCP2 gene-mediated proliferation and apoptosis in osteosarcoma cells.

Ueda J, Ho JC, Lee KL, et al.
The hypoxia-inducible epigenetic regulators Jmjd1a and G9a provide a mechanistic link between angiogenesis and tumor growth.
Mol Cell Biol. 2014; 34(19):3702-20 [PubMed] Free Access to Full Article Related Publications
Hypoxia promotes stem cell maintenance and tumor progression, but it remains unclear how it regulates long-term adaptation toward these processes. We reveal a striking downregulation of the hypoxia-inducible histone H3 lysine 9 (H3K9) demethylase JMJD1A as a hallmark of clinical human germ cell-derived tumors, such as seminomas, yolk sac tumors, and embryonal carcinomas. Jmjd1a was not essential for stem cell self-renewal but played a crucial role as a tumor suppressor in opposition to the hypoxia-regulated oncogenic H3K9 methyltransferase G9a. Importantly, loss of Jmjd1a resulted in increased tumor growth, whereas loss of G9a produced smaller tumors. Pharmacological inhibition of G9a also resulted in attenuation of tumor growth, offering a novel therapeutic strategy for germ cell-derived tumors. Finally, Jmjd1a and G9a drive mutually opposing expression of the antiangiogenic factor genes Robo4, Igfbp4, Notch4, and Tfpi accompanied by changes in H3K9 methylation status. Thus, we demonstrate a novel mechanistic link whereby hypoxia-regulated epigenetic changes are instrumental for the control of tumor growth through coordinated dysregulation of antiangiogenic gene expression.

Praveen Kumar VR, Sehgal P, Thota B, et al.
Insulin like growth factor binding protein 4 promotes GBM progression and regulates key factors involved in EMT and invasion.
J Neurooncol. 2014; 116(3):455-64 [PubMed] Related Publications
Insulin like growth factor binding protein 4 (IGFBP4) regulates growth and development of tissues and organs by negatively regulating IGF signaling. Among most cancers, IGFBP4 has growth inhibitory role and reported as a down-regulated gene, except for renal cell carcinoma, wherein IGFBP4 promotes tumor progression. IGFBP4 expression has been shown to be higher in increasing grades of astrocytoma. However, the functional role of IGFBP4 in gliomas has not been explored. Surgical biopsies of 20 normal brain and 198 astrocytoma samples were analyzed for IGFBP4 expression by qRT-PCR. Highest expression of IGFBP4 mRNA was seen in GBM tumors compared to control brain tissues (median log2 of 2.035, p < 0.0001). Immunohistochemical analysis of 53 tissue samples revealed predominant nuclear staining of IGFBP4, seen maximally in GBMs when compared to DA and AA tumors (median LI = 29.12 ± 16.943, p < 0.001). Over expression of IGFBP4 in U343 glioma cells resulted in up-regulation of molecules involved in tumor growth, EMT and invasion such as pAkt, pErk, Vimentin, and N-cadherin and down-regulation of E-cadherin. Functionally, IGFBP4 over expression in these cells resulted in increased proliferation, migration and invasion as assessed by MTT, transwell migration, and Matrigel invasion assays. These findings were confirmed upon IGFBP4 knockdown in U251 glioma cells. Our data suggest a pro-tumorigenic role for IGFBP4 in glioma.

Feierabend D, Walter J, Grube S, et al.
Methylation-specific multiplex ligation-dependent probe amplification and its impact on clinical findings in medulloblastoma.
J Neurooncol. 2014; 116(2):213-20 [PubMed] Related Publications
Gain of (proto-)oncogenes and loss or promoter hypermethylation of tumor suppressor genes (TSGs) play essential roles in tumorigenesis. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) allows simultaneous detection of both these alterations. MS-MLPA was performed on 20 medulloblastoma samples (n = 12 cryoconserved; n = 8 formalin-fixed paraffin-embedded, FFPE) in order to screen for copy number changes in 77 unselected TSGs and (proto-)oncogenes as well as for promoter hypermethylation in a subset of 33 TSGs. In all specimens, determination of promoter methylation status was possible, whereas robust data concerning copy number changes could be obtained on cryopreserved material only. We found a median of 1.5 deletions and 6.5 amplifications in the 12 cryopreserved medulloblastoma and a median of 5 promoter hypermethylation per tumor. Frequent copy number changes included amplification of ASC on 16p12 (5/12) and amplification of several adjacent genes on 17q (3/12) including IGFBP4. Hypermethylation of MSH6 on 2p16 was found in 16 samples. MS-MLPA findings were also correlated with clinical and histological characteristics. The number of promoter hypermethylation was significantly associated with presence of necrosis (p = 0.004). Tumors which recurred within 1 year were more likely to show amplification of the GATA5 gene (p = 0.038), while hypermethylation of CASP8 was associated with a lower tumor recurrence rate (p = 0.036). There was also a trend towards a correlation between total number of aberrations and CSF dissemination (p = 0.055). Our findings confirm frequent presence of certain aberrations and reveal novel candidates for improving prognosis based on genetic and epigenetic tumor features. A medulloblastoma-specific MS-MLPA probe set seems a potentially valuable tool for further investigations on larger sample series.

Yeh TS, Wang F, Chen TC, et al.
Expression profile of microRNA-200 family in hepatocellular carcinoma with bile duct tumor thrombus.
Ann Surg. 2014; 259(2):346-54 [PubMed] Related Publications
OBJECTIVE: The aim of this study was to assess the role of the miR-200 family in the pathogenesis of hepatocellular carcinoma with bile duct tumor thrombus (HCC-BDTT).
BACKGROUND: Hepatocellular carcinoma with bile duct tumor thrombus is a challenging condition because of its rarity and dismal prognosis. Epithelial-to-mesenchymal transition (EMT) is considered a critical step in the progression and metastasis of HCC and is regulated by the microRNA-200 (miR-200) family.
METHODS: Thirty patients with HCC-BDTT were enrolled and 1240 patients with conventional HCC (cHCC) served as clinicopathologic controls. Sixty age- and sex-matched cHCC patients were selected to compare the miR-200 family expression profile and immunohistochemical characteristics. Gain- and loss-of-function studies of the miR-200 family were conducted using the hepatoma cell lines.
RESULTS: Although the mean size of HCC-BDTT was smaller than that of cHCC, the former had a higher incidence of vascular invasion and a poorer long-term survival. The expressions of miR-200c and miR-141 were downregulated in HCC-BDTT (4.5- and 4.8-fold decrease, respectively). Downregulation of both miR-200c and miR-141 independently predicted disease-free survival. The HCC-BDTT, but not cHCC, exhibited overexpression of ZEB1, Twist, transforming growth factor-β receptor type II, and vimentin, and aberrant E-cadherin expression, indicating EMT. The HCC-BDTT demonstrated increased expression in IL-6 and stemness factor Bmi1, but reduced level of metastasis-suppressive protein, insulin-like growth factor-binding protein 4. The invasive ability of the highly aggressive Mahlavu cell was attenuated by pre-miR-200c+141, whereas the invasive ability of the less aggressive Huh7 cell was enhanced by anti-miR-200c+141.
CONCLUSIONS: Simultaneous silencing of miR-200c and miR-141 was likely to be responsible for the development of HCC-BDTT via ZEB1-directed EMT activation and Sec23a-mediated secretome.

Huang J, Tabata S, Kakiuchi S, et al.
Identification of pregnancy-associated plasma protein A as a migration-promoting gene in malignant pleural mesothelioma cells: a potential therapeutic target.
Oncotarget. 2013; 4(8):1172-84 [PubMed] Free Access to Full Article Related Publications
Despite recent advances in treatment, malignant pleural mesothelioma (MPM) remains a deadly disease. Targeted therapy generated broad interests and is highly expected for the treatment of MPM, yet promising preclinical results have not been translated into substantial clinical benefits for the patients. In this study, we tried to identify the genes which play functional roles in cell migration as well as to test whether they can be used as novel targets for molecular targeted therapy for MPM in preclinical model. In our study, pregnancy-associated plasma protein A (PAPPA) was identified as a gene whose expression level is correlated with MPM cell migration by correlation analysis combining MPM cell migration ability and their gene expression profiles. Highly migratory cells were selected from MPM cell lines, MSTO-211H, NCI-H290 and EHMES-1 in vitro and up-regulation of PAPPA in these cells were confirmed. In vitro, PAPPA was demonstrated to stimulate the MPM cell migration via cleavage of insulin-like growth factor-binding protein-4 and subsequent release of IGF-1. Gene silencing of PAPPA in MPM cells led to reduced migration, invasion and proliferation. Furthermore, PAPPA shRNA transfected NCI-H290 when orthotopically inoculated into pleural cavity of severe combined immunodeficiency recipient mice, failed to develop tumors and produce bloody pleural effusion as control shRNA transfected cells did. Our study suggests that PAPPA plays a functional role in promoting MPM cell migration and it might serve as a potential therapeutic target for the treatment of MPM.

Fellenberg J, Sähr H, Liu L, et al.
Rescue of silenced UCHL1 and IGFBP4 expression suppresses clonogenicity of giant cell tumor-derived stromal cells.
Cancer Lett. 2013; 336(1):61-7 [PubMed] Related Publications
Giant cell tumor (GCT) of bone is a generally benign tumor with a locally aggressive behavior. Histologically, GCTs consist of multinucleated giant cells, mononuclear histiocytes and the neoplastic fibroblast-like stromal cells (GCTSC). Growing evidence exists that GCTSCs develop from mesenchymal stem cells (MSCs), but little is known about the underlying molecular mechanisms. In previous studies we observed inactivation of the ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) gene in primary GCTSC due to strong DNA hypermethylation, indicating that epigenetic silencing might be involved in neoplastic transformation of MSCs. Here we investigated further candidate genes and identified strong hypermethylation of the insulin-like growth factor binding protein 4 (IGFBP4) promoter, resulting in IGFBP4 downregulation in GCTs compared to MSCs. Overexpression of UCHL1 and IGFBP4 by stable transfection of GCTSC did not influence cell viability, proliferation, migration and chemosensitivity compared to parental cells. However, colony-formation was significantly decreased suggesting that rescue of UCHL1 and IFGBP4 suppresses clonogenicity of GCT stromal cells. The observation of reduced expression of the stem-cell-specific transcription factors OCT4 and SOX2 in these cell lines further supported our findings. Epigenetic silencing of UCHL1 and IGFBP4 in GCTs might thus be a crucial event during the malignant transformation of MSCs in the context of GCT development and represent promising targets for the development of new diagnostic and therapeutic strategies.

Matise LA, Palmer TD, Ashby WJ, et al.
Lack of transforming growth factor-β signaling promotes collective cancer cell invasion through tumor-stromal crosstalk.
Breast Cancer Res. 2012; 14(4):R98 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Transforming growth factor beta (TGF-β) has a dual role during tumor progression, initially as a suppressor and then as a promoter. Epithelial TGF-β signaling regulates fibroblast recruitment and activation. Concurrently, TGF-β signaling in stromal fibroblasts suppresses tumorigenesis in adjacent epithelia, while its ablation potentiates tumor formation. Much is known about the contribution of TGF-β signaling to tumorigenesis, yet the role of TGF-β in epithelial-stromal migration during tumor progression is poorly understood. We hypothesize that TGF-β is a critical regulator of tumor-stromal interactions that promote mammary tumor cell migration and invasion.
METHODS: Fluorescently labeled murine mammary carcinoma cells, isolated from either MMTV-PyVmT transforming growth factor-beta receptor II knockout (TβRII KO) or TβRIIfl/fl control mice, were combined with mammary fibroblasts and xenografted onto the chicken embryo chorioallantoic membrane. These combinatorial xenografts were used as a model to study epithelial-stromal crosstalk. Intravital imaging of migration was monitored ex ovo, and metastasis was investigated in ovo. Epithelial RNA from in ovo tumors was isolated by laser capture microdissection and analyzed to identify gene expression changes in response to TGF-β signaling loss.
RESULTS: Intravital microscopy of xenografts revealed that mammary fibroblasts promoted two migratory phenotypes dependent on epithelial TGF-β signaling: single cell/strand migration or collective migration. At epithelial-stromal boundaries, single cell/strand migration of TβRIIfl/fl carcinoma cells was characterized by expression of α-smooth muscle actin and vimentin, while collective migration of TβRII KO carcinoma cells was identified by E-cadherin+/p120+/β-catenin+ clusters. TβRII KO tumors also exhibited a twofold greater metastasis than TβRIIfl/fl tumors, attributed to enhanced extravasation ability. In TβRII KO tumor epithelium compared with TβRIIfl/fl epithelium, Igfbp4 and Tspan13 expression was upregulated while Col1α2, Bmp7, Gng11, Vcan, Tmeff1, and Dsc2 expression was downregulated. Immunoblotting and quantitative PCR analyses on cultured cells validated these targets and correlated Tmeff1 expression with disease progression of TGF-β-insensitive mammary cancer.
CONCLUSION: Fibroblast-stimulated carcinoma cells utilize TGF-β signaling to drive single cell/strand migration but migrate collectively in the absence of TGF-β signaling. These migration patterns involve the signaling regulation of several epithelial-to-mesenchymal transition pathways. Our findings concerning TGF-β signaling in epithelial-stromal interactions are important in identifying migratory mechanisms that can be targeted as recourse for breast cancer treatment.

Becker MA, Hou X, Harrington SC, et al.
IGFBP ratio confers resistance to IGF targeting and correlates with increased invasion and poor outcome in breast tumors.
Clin Cancer Res. 2012; 18(6):1808-17 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To improve the significance of insulin-like growth factor-binding protein 5 (IGFBP-5) as a prognostic and potentially predictive marker in patients with breast cancer.
EXPERIMENTAL DESIGN: Increased IGFBP-5 expression was identified in MCF-7 cells resistant (MCF-7R4) to the IGF-1R/insulin receptor (InsR) inhibitor BMS-536924 and its role examined by targeted knockdown and overexpression in multiple experimental models. Protein expression of IGFBP-5 was measured by immunohistochemistry in a cohort of 76 patients with breast cancer to examine correlative associations with invasive tumor fraction and outcome. The use of a combined IGFBP-5/IGFBP-4 (BPR) expression ratio was applied to predict anti-IGF-1R/InsR response in a panel of breast cancer lines and outcome in multiple breast tumor cohorts.
RESULTS: IGFBP-5 knockdown decreased BMS-536924 resistance in MCF-7R4 cells, whereas IGFBP-5 overexpression in MCF-7 cells conferred resistance. When compared with pathologically normal reduction mammoplasty tissue, IGFBP-5 expression levels were upregulated in both invasive and histologically normal adjacent breast cancer tissue. In both univariate and multivariate modeling, metastasis-free survival, recurrence free survival (RFS), and overall survival (OS) were significantly associated with high IGFBP-5 expression. Prognostic power of IGFBP-5 was further increased with the addition of IGFBP-4 where tumors were ranked based upon IGFBP-5/IGFBP-4 expression ratio (BPR). Multiple breast cancer cohorts confirm that BPR (high vs. low) was a strong predictor of RFS and OS.
CONCLUSION: IGFBP-5 expression is a marker of poor outcome in patients with breast cancer. An IGFBP-5/IGFBP-4 expression ratio may serve as a surrogate biomarker of IGF pathway activation and predict sensitivity to anti-IGF-1R targeting.

Korpal M, Ell BJ, Buffa FM, et al.
Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization.
Nat Med. 2011; 17(9):1101-8 [PubMed] Free Access to Full Article Related Publications
Although the role of miR-200s in regulating E-cadherin expression and epithelial-to-mesenchymal transition is well established, their influence on metastatic colonization remains controversial. Here we have used clinical and experimental models of breast cancer metastasis to discover a pro-metastatic role of miR-200s that goes beyond their regulation of E-cadherin and epithelial phenotype. Overexpression of miR-200s is associated with increased risk of metastasis in breast cancer and promotes metastatic colonization in mouse models, phenotypes that cannot be recapitulated by E-cadherin expression alone. Genomic and proteomic analyses revealed global shifts in gene expression upon miR-200 overexpression toward that of highly metastatic cells. miR-200s promote metastatic colonization partly through direct targeting of Sec23a, which mediates secretion of metastasis-suppressive proteins, including Igfbp4 and Tinagl1, as validated by functional and clinical correlation studies. Overall, these findings suggest a pleiotropic role of miR-200s in promoting metastatic colonization by influencing E-cadherin-dependent epithelial traits and Sec23a-mediated tumor cell secretome.

Rossi E, Klersy C, Manca R, et al.
Correlation between genomic alterations assessed by array comparative genomic hybridization, prognostically informative histologic subtype, stage, and patient survival in gastric cancer.
Hum Pathol. 2011; 42(12):1937-45 [PubMed] Related Publications
It is difficult to evaluate the prognostic value of histologic criteria in gastric cancer because of the high variability of morphologic patterns. Recently, histologic subtypes of low, intermediate, or high malignant potential have been identified, providing the basis for a prognostically informative grading system. Because array comparative genomic hybridization systems allow systematic analysis of chromosome alterations, which may be prognostically and pathogenetically informative, we applied high-resolution genome-wide array comparative genomic hybridization to archival material from 81 gastric cancer cases followed for a median of 150 months after surgery. The DNA extracted from paraffin sections gave useful results in 49 tumors, 18 of which were of low-grade, 24 of intermediate, and 7 of high-grade histotypes. Based on the number of chromosome aberrations and the presence/absence of amplifications, 3 tumor clusters of increasing genomic lesion severity were constructed, which proved to correlate significantly with histologic grade and stage as well as with patient survival. Further investigation documented the lower number and severity of genomic alterations in tumors with microsatellite DNA instability and high CD8-rich lymphoid response; the close association of 8p23.1 amplification with cardial cancer; the frequent amplification of genes involved in cell renewal (CDC6, HER2, GRB7, IGFBP4) at 17q12-q21.1, with close histochemical correlation with HER2 membranous expression; and more sporadic amplification of chromosome regions harboring important oncogenes like MYC, KRAS, NRAS, CRKL, CCNE1, or ZNF217. We conclude that genome-wide array comparative genomic hybridization of gastric cancer contributes prognostically relevant information providing a genetic background for histologic grading.

Wang YC, Yu SQ, Wang XH, et al.
Differences in phenotype and gene expression of prostate stromal cells from patients of varying ages and their influence on tumour formation by prostate epithelial cells.
Asian J Androl. 2011; 13(5):732-41 [PubMed] Free Access to Full Article Related Publications
Prostate cancer (PCa) is an age-related disease, and the stromal microenvironment plays an important role in prostatic malignant progression. However, the differences in prostate stromal cells present in young and old tissue are still obscure. We established primary cultured stromal cells from normal prostatic peripheral zone (PZ) of donors of varying ages and found that cultured stromal cells from old donors (PZ-old) were more enlarged and polygonal than those from young donors (PZ-young). Furthermore, based on immunocytochemical and ultrastructural analysis, the components of stromal cells changed from a majority of fibroblasts to a mixture of fibroblasts and myofibroblasts with increasing donor age. Using a three-dimensional in vitro culture system, we found that PZ-old stromal cells could enhance the proliferation, migration and invasion of cocultured benign BPH-1 and PC-3 cells. Using an in vivo tissue recombination system, we also found that PZ-old stromal cells are more effective than PZ-young cells in promoting tumour formation by BPH-1 cells of high passage (>100) and PC-3 cells. To probe the possible mechanism of these effects, we performed cDNA microarray analysis and profiled 509 upregulated genes and 188 downregulated genes in PZ-old cells. Among the changed genes, we found genes coding for a subset of paracrine factors that are capable of influencing adjacent epithelial cells; these include hepatocyte growth factor (HGF), fibroblast growth factor 5 (FGF5), insulin-like growth factor 2 (IGF2), insulin-like growth factor-binding protein 4 (IGFBP4), IGFBP5 and matrix metallopeptidase 1 (MMP1). Changes in the expression of these genes were further confirmed by quantitative real-time polymerase chain reaction (PCR), Western blotting and enzyme-linked immunosorbent assays. Overall, our findings indicate that stromal cells from prostate PZ of old donors are more active than similar cells from young donors in promoting the malignant process of adjacent epithelial cells. This finding hints at a new potential strategy for the prevention of PCa.

Luo F, Poulogiannis G, Ye H, et al.
Synergism between K-rasVal12 and mutant Apc accelerates murine large intestinal tumourigenesis.
Oncol Rep. 2011; 26(1):125-33 [PubMed] Related Publications
K-ras (KRAS) is mutated in 40-50% of human colorectal adenomas and carcinomas and plays key roles in cell proliferation, apoptosis, motility and differentiation, but its functional contribution to intestinal tumourigenesis in vivo remains incompletely understood. We have previously crossed K-rasVal12 transgenic mice with Ah-Cre mice to produce K-rasVal12/Cre offspring that inducibly express K-rasVal12 4A and 4B in the intestines, but this alone showed no significant effect on intestinal adenoma formation. Here, we crossed these mice with Min mice to evaluate the effect of K-rasVal12 and Apc mutation on intestinal tumourigenesis in vivo. The double mutant K-rasVal12/Cre/ApcMin/+ mice showed a moderate (1.86-fold) increase in adenomas in the small intestines, but a striking acceleration (6-fold increase) of large intestinal adenoma formation (P<0.01) and significantly reduced survival (by ~5 weeks) compared with control ApcMin/+ mice (P<0.01). There was recombination of the mutant K-rasVal12 transgene in 80% of large intestinal adenomas with expression of both K-rasVal12 4A and 4B isoform transcripts and expression of K-RasVal12 protein. The large intestinal adenomas showed immunohistochemical evidence of activation of MapK, Akt and Wnt signaling pathways and this was confirmed by quantitative RT-PCR analysis of relative transcript expression levels of target genes using a panel of 23 selected genes evaluated in both adenomas and non-tumour-bearing intestines. Several genes including Tiam1, Gastrin, CD44, uPA, Igfbp4, VEGF and Cox-2 that are known to be transcriptionally regulated by activation of the Wnt signaling pathway were found to be expressed at higher levels in the large intestinal adenomas from K-rasVal12/Cre/ApcMin/+ mice compared with those from controls, although other Wnt signaling pathway target genes remained unchanged. These data show that intestinal expression of K-rasVal12 accelerates Apc-initiated intestinal adenomagenesis in vivo with particularly striking tumour promotion in the large intestines and indicate synergistic effects between mutant K-ras and mutant Apc in this process.

Romero D, O'Neill C, Terzic A, et al.
Endoglin regulates cancer-stromal cell interactions in prostate tumors.
Cancer Res. 2011; 71(10):3482-93 [PubMed] Free Access to Full Article Related Publications
Endoglin is an accessory receptor for TGF-β that has been implicated in prostate cancer cell detachment, migration, and invasiveness. However, the pathophysiologic significance of endoglin with respect to prostate tumorigenesis has yet to be fully established. In this study, we addressed this question by investigation of endoglin-dependent prostate cancer progression in a TRAMP (transgenic adenocarcinoma mouse prostate) mouse model where endoglin was genetically deleted. In this model, endoglin was haploinsufficient such that its allelic deletion slightly increased the frequency of tumorigenesis, yet produced smaller, less vascularized, and less metastatic tumors than TRAMP control tumors. Most strikingly, TRAMP:eng(+/-)-derived tumors lacked the pronounced infiltration of carcinoma-associated fibroblasts (CAF) that characterize TRAMP prostate tumors. Studies in human primary prostate-derived stromal cells (PrSC) confirmed that suppressing endoglin expression decreased cell proliferation, the ability to recruit endothelial cells, and the ability to migrate in response to tumor cell-conditioned medium. We found increased levels of secreted insulin-like growth factor-binding proteins (IGFBP) in the conditioned medium from endoglin-deficient PrSCs and that endoglin-dependent regulation of IGFBP-4 secretion was crucial for stromal cell-conditioned media to stimulate prostate tumor cell growth. Together, our results firmly establish the pathophysiologic involvement of endoglin in prostate cancer progression; furthermore, they show how endoglin acts to support the viability of tumor-infiltrating CAFs in the tumor microenvironment to promote neovascularization and growth.

Lamy PJ, Fina F, Bascoul-Mollevi C, et al.
Quantification and clinical relevance of gene amplification at chromosome 17q12-q21 in human epidermal growth factor receptor 2-amplified breast cancers.
Breast Cancer Res. 2011; 13(1):R15 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Human epidermal growth factor receptor 2 (HER2)-amplified breast cancers represent a tumor subtype with chromosome 17q rearrangements that lead to frequent gene amplifications. The aim of this study was to quantify the amplification of genes located on chromosome 17q and to analyze the relations between the pattern of gene amplifications and the patients' characteristics and survival.
METHODS: Patients with HER2-positive breast tumors (HER2 score of 3+ by immunohistochemistry or positive for HER2 amplification by fluorescence in situ hybridization (FISH)) (n = 86) and with HER2-negative breast tumors (n = 40) (negative controls) were included in this study. Using a quantitative polymerase chain reaction method and DNA extracted from frozen tumor specimens, 11 genes (MED1, STARD3, HER2, GRB7, THRA, RARA, TOP2A, IGFBP4, CCR7, KRT20, KRT19 and GAS), which are localized within Chr17q12-q21 and have a putative role in breast cancer development, were quantified. Relapse-free and overall survival rates were estimated from the date of surgery to the date of the event of interest (recurrence or death) using the Kaplan-Meier method.
RESULTS: Gene amplification was observed only in HER2-positive tumors, and the frequency of amplification decreased with the distance of the gene from HER2. HER2 presented the highest level of amplification. TOP2A was not included in the smallest region of amplification involving HER2. Amplification of RARA, KRT20 and KRT19 was significantly associated with node-positive breast cancer (P = 0.030, P = 0.002 and P = 0.033, respectively). During a median follow-up period of 55 months (range, 6 to 81 months), the subgroup of patients with hormone receptor-negative cancer and without TOP2A amplification showed the worst survival (relapse-free survival: hazard ratio (HR) = 0.29, 95% confidence interval (95% CI), 0.13 to 0.65, P = 0.001; and overall survival: HR = 0.28, 95% CI, 0.10 to 0.76, P = 0.008).
CONCLUSIONS: HER2 amplification seems to drive genomic instability along chromosome 17q, leading to different patterns of gene amplification. This study confirms the clinical importance of identifying, among patients with HER2-positive breast tumors, the subgroup of patients with hormone receptor-negative and nonamplified TOP2A cancers as they have the worst prognosis.

Ueno K, Hirata H, Majid S, et al.
IGFBP-4 activates the Wnt/beta-catenin signaling pathway and induces M-CAM expression in human renal cell carcinoma.
Int J Cancer. 2011; 129(10):2360-9 [PubMed] Related Publications
The Wnt/β-catenin signaling pathway is inactivated by Wnt antagonists in most cancers and IGFBP-4 is an antagonist of the Wnt/ β-catenin signaling pathway. However, the function of IGFBP-4 is not currently understood in renal cell carcinoma (RCC). We initially found that the expression of IGFBP-4 was significantly lower in primary RCC and higher in metastatic RCC compared to normal human kidney tissues. To assess the function of IGFBP4, we established IGFBP4 transfectants (primary renal cancer cell line) and performed functional analyses including Tcf reporter assays, cell viability, invasive capability, mortality, and in vivo tumor growth. Interestingly IGFBP-4 transfectants promoted cell growth (in vitro and in vivo), invasion, and motility in primary renal cancer. Tcf transcriptional activity was significantly increased in IGFBP-4 transfectants compared to mock cells and β-catenin expression was increased. Also the β-catenin downstream effector, MT1-MMP showed increased expression in IGFBP4 transfectants. Additionally IGFBP4 induced the expression of M-CAM, a marker of tumor progression. In order to assess the role of IGFBP4 in metastatic renal cancer, IGFBP-4 mRNA in a metastatic renal cancer cell lines (ACHN) was knocked-down using a siRNA technique. The cell growth and motility was decreased in si-IGFBP4 transfected ACHN cells compared to cells transfected with control siRNA. Tcf activity in ACHN cells was also decreased with si-IGFBP-4 transfection. This is a first report documenting that IGFBP-4 expression in RCC activates cell growth, metastasis, Wnt/beta-catenin signaling and may be involved in RCC metastasis.

Sato H, Sakaeda M, Ishii J, et al.
Insulin-like growth factor binding protein-4 gene silencing in lung adenocarcinomas.
Pathol Int. 2011; 61(1):19-27 [PubMed] Related Publications
Gene silencing by promoter hypermethylation plays an important role in molecular pathogenesis. We previously reported that insulin-like growth factor (IGF) binding protein-4 (IGFBP-4), which inhibits IGF-dependent growth, is expressed via early growth response-1 (EGR-1) and is often silenced in cultivated lung cancer cells. The purpose of the present study was to clarify clinicopathological factors associated with IGFBP-4 gene silencing in lung adenocarcinomas. Seventy-six surgically resected adenocarcinomas (20 well-, 35 moderately-, and 21 poorly-differentiated) were subjected to methylation-specific polymerase chain reaction (PCR) analysis for EGR-1-binding sites located in the IGFBP-4 promoter and immunohistochemistry for IGFBP-4, EGR-1, and Ki-67. Thirty-two adenocarcinomas (42%) revealed IGFBP-4 promoter hypermethylation, and the severity inversely correlated with the level of IGFBP-4 expression (P < 0.0001) and tumor differentiation (well versus poor, P = 0.0278; well/moderate versus poor, P = 0.0395). Furthermore, there was a negative correlation between Ki-67 labeling index and IGFBP-4 expression (P = 0.0361). These findings suggest that the expression of IGFBP-4 in adenocarcinoma cells in vivo is downregulated by epigenetic silencing in association with tumor differentiation, resulting in disruption of the mechanism of IGFBP-4-mediated growth inhibition.

Zhou GD, Richardson M, Fazili IS, et al.
Role of retinoic acid in the modulation of benzo(a)pyrene-DNA adducts in human hepatoma cells: implications for cancer prevention.
Toxicol Appl Pharmacol. 2010; 249(3):224-30 [PubMed] Free Access to Full Article Related Publications
Carcinogen-DNA adducts could lead to mutations in critical genes, eventually resulting in cancer. Many studies have shown that retinoic acid (RA) plays an important role in inducing cell apoptosis. Here we have tested the hypothesis that levels of carcinogen-DNA adducts can be diminished by DNA repair and/or by eliminating damaged cells through apoptosis. Our results showed that the levels of total DNA adducts in HepG2 cells treated with benzo(a)pyrene (BP, 2 μM)+RA (1 μM) were significantly reduced compared to those treated with BP only (P=0.038). In order to understand the mechanism of attenuation of DNA adducts, further experiments were performed. Cells were treated with BP (4 μM) for 24h to initiate DNA adduct formation, following which the medium containing BP was removed, and fresh medium containing 1 μM RA was added. The cells were harvested 24h after RA treatment. Interestingly, the levels of total DNA adducts were lower in the BP/RA group (390 ± 34) than those in the BP/DMSO group (544 ± 33), P=0.032. Analysis of cell apoptosis showed an increase in BP+RA group, compared to BP or RA only groups. Our results also indicated that attenuation of BP-DNA adducts by RA was not primarily due to its effects on CYP1A1 expression. In conclusion, our results suggest a mechanistic link between cellular apoptosis and DNA adduct formation, phenomena that play important roles in BP-mediated carcinogenesis. Furthermore, these results help understand the mechanisms of carcinogenesis, especially in relation to the chemopreventive properties of nutritional apoptosis inducers.

Xie HL, Li ZY, Gan RL, et al.
Differential gene and protein expression in primary gastric carcinomas and their lymph node metastases as revealed by combined cDNA microarray and tissue microarray analysis.
J Dig Dis. 2010; 11(3):167-75 [PubMed] Related Publications
OBJECTIVE: To gain insight into the molecular events of lymph node metastasis of human gastric carcinoma.
METHODS: The gene expression profile of five matched primary gastric carcinomas and their lymph node metastases was analyzed by complementary DNA (cDNA) microarray. Differential genes were identified in the metastatic and corresponding primary tumor pairs. Among the differentially expressed genes, carbonic anhydrase II (CAII) and insulin-like growth factor binding protein 4 (IGFBP 4) genes were detected by RT-PCR. CTTN protein expression was examined by tissue microarray.
RESULTS: There was a high expression (over twofold) of 44 genes and a low expression (under twofold) of 32 genes in lymph node metastasis compared with primary gastric carcinoma, respectively. CAII mRNA was downregulated and IGFBP 4 mRNA was upregulated in paired lymph node metastases of gastric carcinomas. The overexpression of CTTN protein was related to the lymph node metastasis and the clinical stage of gastric carcinomas.
CONCLUSION: This study showed that there is a low expression of genes relative to growth signal and immune response in lymph node metastases, and a high expression of genes relative to growth factor, cell cycle, cell motility and adhesion in lymph node metastases compared with primary gastric carcinomas. The expression of CTTN was related to the invasion and metastasis of gastric cancer.

Kwon H, Choi DH, Bae JH, et al.
mRNA expression pattern of insulin-like growth factor components of granulosa cells and cumulus cells in women with and without polycystic ovary syndrome according to oocyte maturity.
Fertil Steril. 2010; 94(6):2417-20 [PubMed] Related Publications
The mRNA expression of insulin-like growth factor (IGF) components was investigated in granulosa cells (GCs) and cumulus cells (CCs) sampled from immature and mature follicles in women with and without polycystic ovary syndrome (PCOS). Gene expression for IGF-binding protein (IGFBP) 3 in GCs definitely differed between normal women and women with PCOS, whereas increase in IGF-I and IGF receptor (IGFR) 2 mRNA in mature-follicle GCs, increase in IGF-II, IGFR-1, and IGFBP-4 mRNA in immature-follicle GCs, increase in IGFR-2 and IGFBP-2 mRNA in mature-follicle CCs, and increase IGFBP-6 mRNA in immature-follicle CCs were observed in both normal women and women with PCOS.

Bartling B, Koch A, Simm A, et al.
Insulin-like growth factor binding proteins-2 and -4 enhance the migration of human CD34-/CD133+ hematopoietic stem and progenitor cells.
Int J Mol Med. 2010; 25(1):89-96 [PubMed] Related Publications
The insulin-like growth factor (IGF) system is involved in cell migration, which plays an important role in cancer progression. It has been shown that cancer progression correlates with the level of circulating human hematopoietic stem and progenitor cells (HSPCs) expressing CD34 and/or CD133. However, it is unknown whether factors released from cancer cells, including soluble compounds of the IGF system, recruit these HSPCs via enhancing their migration. Our study showed the expression of type I IGF receptor (IGF-IR) in human HSPCs expressing CD34 and/or CD133. In an indirect co-culture model, soluble factors released from human lung epithelial cancer cells (H358, H322) increased the migration of CD34-/CD133+ cells towards cancer cells, whereas migration of CD34+/CD133+ or CD34+/CD133- cells remained unchanged. The lung epithelial cancer cell lines H358 and H322, exhibited a high expression of IGFBP-2, -4 and -6 but not IGF-I and IGFBP-3. Subsequent analyses with those soluble compounds of the IGF system revealed a dose-dependent stimulating effect of the IGFBP-2 and -4 on the migration of CD34-/CD133+ cells. In contrast, IGF-I and IGFBP-3 and -6 did not influence the migration of CD34-/CD133+ cells. Because IGFBPs are involved in cell migration via IGF-dependent and -independent mechanisms, our study indicates that IGFBP-2 and -4, which are expressed in lung epithelial cancer cells, enhance the migration of CD34-/CD133+ HSPCs independent of IGF-I.

Lee S, Kang J, Cho M, et al.
Profiling of transcripts and proteins modulated by K-ras oncogene in the lung tissues of K-ras transgenic mice by omics approaches.
Int J Oncol. 2009; 34(1):161-72 [PubMed] Related Publications
The mutated K-ras gene is involved in approximately 30% of human cancers. In order to search for K-ras oncogene-induced modulators in lung tissues of K-ras transgenic mice, we performed microarray and proteomics (LC/ESI-MS/MS) analysis. Genes (RAB27b RAS family, IL-1RA, IL-33, chemokine ligand 6, epiregulin, EGF-like domain and cathepsin) related to cancer development (Wnt signaling pathway) and inflammation (chemokine/cytokine signaling pathway, Toll receptor signaling) were up-regulated while genes (troponin, tropomodulin 2, endothelial lipase, FGFR4, integrin alpha8 and adenylate cyclase 8) related to the tumor suppression such as p53 pathway, TGF-beta signaling pathway and cadherin signaling pathway were down-regulated by K-ras oncogene. Proteomics approach revealed that up-regulated proteins in lung adenomas of K-ras mice were classified as follows: proteins related to the metabolism/catabolism (increased from 7 to 22% by K-ras gene), proteins related to translation/transcription and nucleotide (from 4 to 6%), proteins related to signal transduction (from 3 to 5%), proteins related to phosphorylation (from 1 to 2%). ATP synthase, Ras oncogene family, cytochrome c oxidase, flavoprotein, TEF 1, adipoprotein A-1 BP, glutathione oxidase, fatty acid BP 4, diaphorase 1, MAPK4 and transgelin were up-regulated by K-ras oncogene. However, integrin alpha1, Ras-interacting protein (Rain), endothelin-converting enzyme-1d and splicing factor 3b were down-regulated. These studies suggest that genes related to cancer development and inflammation were up-regulated while genes related to the tumor suppression were down-regulated by K-ras, resulting in the tumor growth. Putative biomarkers such as cell cycle related genes (Cdc37), cancer cell adhesion (Glycam 1, integrin alpha8, integrin alphaX and Clec4n), signal transduction (Tlr2, IL-33, and Ccbp2), migration (Ccr1, Ccl6, and diaphorase 1 (Cyb5r3) and cancer development (epiregulin) can be useful for diagnosis and as prognosis markers and some of the target molecules can be applied for prevention of cancer.

Vendrell JA, Robertson KE, Ravel P, et al.
A candidate molecular signature associated with tamoxifen failure in primary breast cancer.
Breast Cancer Res. 2008; 10(5):R88 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Few markers are available that can predict response to tamoxifen treatment in estrogen receptor (ER)-positive breast cancers. Identification of such markers would be clinically useful. We attempted to identify molecular markers associated with tamoxifen failure in breast cancer.
METHODS: Eighteen initially ER-positive patients treated with tamoxifen requiring salvage surgery (tamoxifen failure [TF] patients) were compared with 17 patients who were disease free 5 years after surgery plus tamoxifen adjuvant therapy (control patients). cDNA microarray, real-time quantitative PCR, and immunohistochemistry on tissue microarrays were used to generate and confirm a gene signature associated with tamoxifen failure. An independent series of 33 breast tumor samples from patients who relapsed (n = 14) or did not relapse (n = 19) under tamoxifen treatment from a different geographic location was subsequently used to explore the gene expression signature identified.
RESULTS: Using a screening set of 18 tumor samples (from eight control patients and 10 TF patients), a 47-gene signature discriminating between TF and control samples was identified using cDNA arrays. In addition to ESR1/ERalpha, the top-ranked genes selected by statistical cross-analyses were MET, FOS, SNCG, IGFBP4, and BCL2, which were subsequently validated in a larger set of tumor samples (from 17 control patients and 18 TF patients). Confirmation at the protein level by tissue microarray immunohistochemistry was observed for ER-alpha, gamma-synuclein, and insulin-like growth factor binding protein 4 proteins in the 35 original samples. In an independent series of breast tumor samples (19 nonrelapsing and 14 relapsing), reduced expression of ESR1/ERalpha, IGFBP4, SNCG, BCL2, and FOS was observed in the relapsing group and was associated with a shorter overall survival. Low mRNA expression levels of ESR1/ERalpha, BCL2, and FOS were also associated with a shorter relapse-free survival (RFS). Using a Cox multivariate regression analysis, we identified BCL2 and FOS as independent prognostic markers associated with RFS. Finally, the BCL2/FOS signature was demonstrated to have more accurate prognostic value for RFS than ESR1/ERalpha alone (likelihood ratio test).
CONCLUSIONS: We identified molecular markers including a BCL2/FOS signature associated with tamoxifen failure; these markers may have clinical potential in the management of ER-positive breast cancer.

Marchiò C, Natrajan R, Shiu KK, et al.
The genomic profile of HER2-amplified breast cancers: the influence of ER status.
J Pathol. 2008; 216(4):399-407 [PubMed] Related Publications
Expression profiling studies have suggested that HER2-amplified breast cancers constitute a heterogeneous group that may be subdivided according to their ER status: HER2-amplified ER-positive breast carcinomas that fall into the luminal B cluster; and HER2-amplified ER-negative cancers which form a distinct molecular subgroup, known as the erbB2 or HER2 subgroup. ER-negative breast cancer differs significantly from ER-positive disease in the pattern, type, and complexity of genetic aberrations. Here we have compared the genomic profiles of ER-positive and ER-negative HER2-amplified cancers using tiling path microarray-based comparative genomic hybridization (aCGH). Validation of the differentially amplified regions was performed in an independent series of 70 HER2-amplified breast cancers. Although HER2-amplified cancers had remarkably complex patterns of molecular genetic aberrations, ER-positive and ER-negative HER2-amplified breast carcinomas shared most molecular genetic features as defined by aCGH. Genome-wide Fisher's exact test analysis revealed that less than 1.5% of the genome was significantly differentially gained or lost in ER-positive versus ER-negative HER2-amplified cancers. However, two regions of amplification were significantly associated with ER-positive carcinomas, one of which mapped to 17q21.2 and encompassed GJC1, IGFBP4, TNS4, and TOP2A. Chromogenic in situ hybridization analysis of an independent validation series confirmed the association between ER status and TOP2A amplification. In conclusion, although hormone receptor status does not determine the overall genetic profile of HER2-amplified breast cancers, specific genetic aberrations may be characteristic of subgroups of HER2 breast cancers.

Guix M, Faber AC, Wang SE, et al.
Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins.
J Clin Invest. 2008; 118(7):2609-19 [PubMed] Free Access to Full Article Related Publications
Although some cancers are initially sensitive to EGFR tyrosine kinase inhibitors (TKIs), resistance invariably develops. We investigated mechanisms of acquired resistance to the EGFR TKI gefitinib by generating gefitinib-resistant (GR) A431 squamous cancer cells. In GR cells, gefitinib reduced phosphorylation of EGFR, ErbB-3, and Erk but not Akt. These cells also showed hyperphosphorylation of the IGFI receptor (IGFIR) and constitutive association of IRS-1 with PI3K. Inhibition of IGFIR signaling disrupted the association of IRS-1 with PI3K and restored the ability of gefitinib to downregulate PI3K/Akt signaling and to inhibit GR cell growth. Gene expression analyses revealed that GR cells exhibited markedly reduced IGF-binding protein 3 (IGFBP-3) and IGFBP-4 RNA. Addition of recombinant IGFBP-3 restored the ability of gefitinib to downregulate PI3K/Akt signaling and to inhibit cell growth. Finally, gefitinib treatment of mice with A431 xenografts in combination with an IGFIR-specific monoclonal antibody prevented tumor recurrence, whereas each drug given alone was unable to do so. These data suggest that loss of expression of IGFBPs in tumor cells treated with EGFR TKIs derepresses IGFIR signaling, which in turn mediates resistance to EGFR antagonists. Moreover, combined therapeutic inhibition of EGFR and IGFIR may abrogate this acquired mechanism of drug resistance and is thus worthy of prospective clinical investigation.

de Bont JM, van Doorn J, Reddingius RE, et al.
Various components of the insulin-like growth factor system in tumor tissue, cerebrospinal fluid and peripheral blood of pediatric medulloblastoma and ependymoma patients.
Int J Cancer. 2008; 123(3):594-600 [PubMed] Related Publications
The insulin-like growth factor (IGF) system plays an important role in neuronal development and may contribute to the development of brain tumors. In this study, we studied mRNA expression levels of IGFs, insulin-like growth factor binding proteins (IGFBPs) and insulin-like growth factor receptors (IGFRs) in 27 pediatric medulloblastomas, 13 pediatric ependymomas and 5 control cerebella. Compared to normal cerebellum, mRNA levels of IGFBP-2 and IGFBP-3 were significantly increased in medulloblastomas and ependymomas. IGFBP-2 expression was indicative of poor prognosis in medulloblastomas, whereas IGFBP-3 mRNA levels were especially high in anaplastic ependymomas. IGFBP-5 and IGF-II mRNA levels were significantly increased in ependymomas compared to control cerebellum. Protein expression levels of IGFs and IGFBPs were analyzed in the cerebrospinal fluid (CSF) of 16 medulloblastoma, 4 ependymoma and 23 control patients by radioimmuno assay to determine whether they could be used as markers for residual disease after surgery. No aberrant CSF protein expression levels were found for ependymoma patients. In medulloblastoma patients, the IGFBP-3 protein levels were significantly higher than in ependymoma patients and controls. Moreover, enhanced levels of proteolytic fragments of IGFBP-3 were found in the CSF of medulloblastoma patients, being in concordance with a significantly increased IGFBP-3 proteolytic activity in the CSF of these patients. In conclusion, our data suggest that the IGF system is of importance in pediatric medulloblastomas and ependymomas. Larger studies should be conducted to validate the predictive values of the levels of intact IGFBP-3 and proteolytic fragments in CSF in the follow-up of medulloblastomas.

Durai R, Yang SY, Sales KM, et al.
Increased apoptosis and decreased proliferation of colorectal cancer cells using insulin-like growth factor binding protein-4 gene delivered locally by gene transfer.
Colorectal Dis. 2007; 9(7):625-31 [PubMed] Related Publications
OBJECTIVE: Insulin-like growth factor (IGF)-I induces proliferation of transformed cells. Its binding proteins (IGFBP) are involved in local regulation of IGF. This study assessed the effects of overexpression of IGFBP-4 on the development of cancer in vivo.
METHOD: Nude mice were subcutaneously inoculated with HT-29 colorectal cancer cells (3 x 10(6)). When the tumour became visible (1 week after inoculation), animals received either 150 microg of mammalian expression vector containing IGFBP-4 cDNA or vector alone (n = 6 each) by peritumoural injection. Tumour size was measured during the growth. After 3 weeks of IGFBP-4 induction, animals were killed and tumour tissue samples were collected for examining the level of IGFBP-4 expression. Tumour mitotic activities were determined by counting numbers of mitotic cells on the tissue section. Apoptosis was investigated by terminal deoxynucleotidyl transferase-mediated dUDP nick end labelling assay.
RESULTS: Following IGFBP-4 treatment, tumour showed large necrotic areas, significantly increased numbers of apoptotic cells (36.67 +/- 7.36 vs 7.07 +/- 1.91, P < 0.01 vs control), decreased cells undergoing mitosis (2.31 +/- 0.32 vs 3.61 +/- 0.27, P < 0.01 vs control) and higher expression of IGFBP-4 (P < 0.05 vs control).
CONCLUSION: IGFBP-4 gene transfer increased apoptosis and decreased mitosis, but tumour volume was not significantly altered possibly due to cellular debris filling the centre of tumours.

Mita K, Zhang Z, Ando Y, et al.
Prognostic significance of insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5 expression in breast cancer.
Jpn J Clin Oncol. 2007; 37(8):575-82 [PubMed] Related Publications
BACKGROUND: Expression of estrogen-regulated genes has been considered as potential predictive markers for endocrine therapy. We focused on two insulin-like growth factor binding proteins (IGFBPs): IGFBP-4, which is an early-responsive estrogen-induced gene, and IGFBP-5, which is an estrogen-repressed gene. Investigation of IGFBP-4 and IGFBP-5 expression would provide important information for predicting prognosis and endocrine responsiveness.
METHODS: The levels of IGFBP-4 and IGFBP-5 mRNA expression in 162 human breast cancer tissues were analyzed using quantitative real-time reverse transcriptase-PCR. The association between IGFBP-4 and IGFBP-5 expression and clinicopathological factors was then analyzed.
RESULTS: The levels of IGFBP-4 and IGFBP-5 mRNA expression were positively correlated with estrogen receptor (ER) and progesterone receptor (PgR) status and were negatively correlated with HER2 overexpression. Patients with a high level of IGFBP-4 mRNA expression had better disease-free and overall survival than those with a low expression. Multivariate analysis showed that IGFBP-4 mRNA expression is an independent prognostic factor for disease-free survival. When analyzed in 116 patients with ER-positive breast cancer, patients whose tumor expressed higher levels of IGFBP-4 mRNA or lower levels of IGFBP-5 mRNA had better disease-free survival.
CONCLUSION: IGFBP-4 mRNA expression was an independent prognostic factor in breast cancer, and patients with ER-positive breast cancer whose tumor expressed higher levels of IGFBP-4 and lower levels of IGFBP-5 had a better prognosis than those without such findings.

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