IGFBP1

Gene Summary

Gene:IGFBP1; insulin-like growth factor binding protein 1
Aliases: AFBP, IBP1, PP12, IGF-BP25, hIGFBP-1
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 binds both insulin-like growth factors (IGFs) I and II and circulates in the plasma. 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:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:insulin-like growth factor-binding protein 1
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.

  • Genetic Variation
  • Tumor Markers
  • Gene Expression Regulation
  • Insulin-Like Growth Factor Binding Proteins
  • Polymorphism
  • Chromosome 7
  • Genetic Predisposition
  • Insulin
  • Tyrosine 3-Monooxygenase
  • Hepatocellular Carcinoma
  • Insulin-Like Growth Factor Binding Protein 3
  • Insulin-Like Growth Factor Binding Protein 1
  • Cohort Studies
  • Ovarian Cancer
  • Single Nucleotide Polymorphism
  • Thailand
  • Insulin-Like Growth Factor I
  • Somatomedins
  • Gene Expression Profiling
  • RTPCR
  • Puberty
  • Gene Expression
  • Sweden
  • Liver Cancer
  • Promoter Regions
  • Base Sequence
  • Liver
  • Case-Control Studies
  • Insulin-Like Growth Factor Binding Protein 2
  • Carrier Proteins
  • IGF2
  • Cancer Gene Expression Regulation
  • Breast Cancer
  • Prostate Cancer
  • WT1
  • Genotype
  • Oligonucleotide Array Sequence Analysis
  • Messenger RNA
  • Molecular Sequence Data
  • Immunohistochemistry
Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: IGFBP1 (cancer-related)

Ozhand A, Lee E, Wu AH, et al.
Variation in inflammatory cytokine/growth-factor genes and mammographic density in premenopausal women aged 50-55.
PLoS One. 2013; 8(6):e65313 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mammographic density (MD) has been found to be an independent risk factor for breast cancer. Although data from twin studies suggest that MD has a strong genetic component, the exact genes involved remain to be identified. Alterations in stromal composition and the number of epithelial cells are the most predominant histopathological determinants of mammographic density. Interactions between the breast stroma and epithelium are critically important in the maturation and development of the mammary gland and the cross-talk between these cells are mediated by paracrine growth factors and cytokines. The potential impact of genetic variation in growth factors and cytokines on MD is largely unknown.
METHODS: We investigated the association between 89 single nucleotide polymorphisms (SNPs) in 7 cytokine/growth-factor genes (FGFR2, IGFBP1, IGFBP3, TGFB1, TNF, VEGF, IL6) and percent MD in 301 premenopausal women (aged 50 to 55 years) participating in the Norwegian Breast Cancer Screening Program. We evaluated the suggestive associations in 216 premenopausal Singapore Chinese Women of the same age.
RESULTS: We found statistically significant associations between 9 tagging SNPs in the IL6 gene and MD in Norwegian women; the effect ranged from 3-5% in MD per variant allele (p-values = 0.02 to 0.0002). One SNP in the IL6 (rs10242595) significantly influenced MD in Singapore Chinese women.
CONCLUSION: Genetic variations in IL6 may be associated with MD and therefore may be an indicator of breast cancer risk in premenopausal women.

Levine AJ, Ihenacho U, Lee W, et al.
Genetic variation in insulin pathway genes and distal colorectal adenoma risk.
Int J Colorectal Dis. 2012; 27(12):1587-95 [PubMed] Related Publications
BACKGROUND: Insulin, glucose, and other insulin-related proteins that mediate insulin signaling are associated with colorectal neoplasia risk, but associations with common genetic variation in insulin axis genes are less clear. In this study, we used a comprehensive tag single-nucleotide polymorphisms (SNPs) approach to define genetic variation in six insulin axis genes (IGF1, IGF2, IGFBP1, IGFBP3, IRS1, and IRS2) and three genes associated with estrogen signaling (ESR1, ESR2, and PGR).
METHODS: We assessed associations between SNPs and distal colorectal adenoma (CRA) risk in a case-control study of 1,351 subjects. Cases were individuals with one or more adenomas diagnosed during sigmoidoscopy, and controls were individuals with no adenomas at the sigmoidoscopy exam. We used unconditional logistic regression assuming an additive model to assess SNP-specific risks adjusting for multiple comparisons with P (act).
RESULTS: Distal adenoma risk was significantly increased for one SNP in IGF2 [per minor allele OR = 1.41; 95 % confidence interval (CI) = 1.16, 1.67; P (act) = 0.005] and decreased for an ESR2 SNP (per minor allele OR = 0.78; 95 % CI = 0.66, 0.91; P (act) = 0.041). There was no statistically significant heterogeneity of these associations by race, sex, BMI, physical activity, or, in women, hormone replacement therapy use. Risk estimates did not differ in the colon versus rectum or for smaller (<1 cm) versus larger (>1 cm) adenomas.
CONCLUSIONS: These data suggest that selected genetic variability in IGF2 and ESR2 may be modifiers of CRA risk.

Rauchfuss F, Lambeck S, Claus RA, et al.
Sustained liver regeneration after portal vein embolization --a human molecular pilot study.
Dig Liver Dis. 2012; 44(8):681-8 [PubMed] Related Publications
BACKGROUND: Portal vein embolization is a treatment option to achieve a sufficient future remnant liver volume for patients with central liver tumours requiring an extended resection with an extensive parenchymal loss. However, molecular mechanisms of this intervention are up to now poorly understood. The objective of this prospective pilot study was the characterization of molecular events leading to late hypertrophy of the non-embolized liver tissue in the human liver.
METHODS: Liver tissue of ten patients was collected before and intraoperatively more than one month after embolization. Investigation of molecular features was performed by pangenomic chips, polymerase chain reaction, immunostaining of proliferation marker Ki-67 and immunofluorescence measurements.
RESULTS: Significantly elevated genes hint towards angiogenesis and signalling by insulin-like growth factor and associated binding proteins. Increased transcript levels of activator protein 1 complex members like c-jun were reflecting potential molecular events of liver growth after embolization. Immunofluorescence data confirmed a predominant upregulation of β-catenin and c-jun (p<0.1) supported by Ki-67 (p<0.05) in the non-embolized liver. In silico analysis of transcriptomic dysplasia and hepatocellular carcinoma data showed divergent signatures compared to embolization.
CONCLUSIONS: Our findings indicate a sustained regeneration after portal vein embolization reflected in hyperplasia and angiogenesis in the human liver and provide novel molecular mechanisms of interlobe crosstalk.

Chen YJ, Chen CC, Li TK, et al.
Docosahexaenoic acid suppresses the expression of FoxO and its target genes.
J Nutr Biochem. 2012; 23(12):1609-16 [PubMed] Related Publications
Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, has previously been shown to ameliorate obesity-associated metabolic syndrome. To decipher the mechanism responsible for the beneficial effects of DHA on energy/glucose homeostasis and the metabolic syndrome, 30 weaned cross-bred pigs were randomly assigned to three groups and fed ad libitum with a standard diet supplemented with 2% of beef tallow, soybean oil or DHA oil for 30 days, and the gene expression profile of various tissues was evaluated by quantitative real-time polymerase chain reaction. The DHA-supplemented diets reduced the expression of forkhead box O transcription factor (FoxO) 1 and FoxO3 in the liver and adipose tissue. DHA treatments also decreased the expression of FoxO1 and FoxO3 in human hepatoma cells, SK-HEP-1 and human and porcine primary adipocytes. In addition, DHA also down-regulated FoxO target genes, such as microsomal triacylglycerol transfer protein (MTP), glucose-6-phosphatase, apolipoprotein C-III (apoC-III) and insulin-like growth factor binding-protein 1 in the liver, as well as reduced total plasma levels of cholesterol and triacylglycerol in the pig. Transcriptional suppression of FoxO1, FoxO3, apoC-III and MTP by DHA was further confirmed by reporter assays with each promoter construct. Taken together, our study indicates that DHA modulates lipid and glucose homeostasis in part by down-regulating FoxO function. The down-regulation of genes associated with triacylglycerol metabolism and very low density lipoprotein assembly is likely to contribute to the beneficial effects of DHA on the metabolic syndrome.

Ziebarth AJ, Landen CN, Alvarez RD
Molecular/genetic therapies in ovarian cancer: future opportunities and challenges.
Clin Obstet Gynecol. 2012; 55(1):156-72 [PubMed] Related Publications
Ovarian cancer is the most lethal gynecologic cancer. Traditional therapies have included surgical management and cytotoxic chemotherapy; however, treatment paradigms continue to shift from empiric cytotoxic chemotherapy to more individualized treatment. Recent research efforts have focused on determining and targeting the molecular biological mechanisms of ovarian cancer in an attempt to develop novel therapeutic modalities with the ultimate goal of improving outcome while limiting toxicity. This chapter reviews progress in the development of novel therapies directed at major pathways implicated in ovarian tumorigenesis including angiogenesis, PARP inhibition, signal transduction, antifolate therapies, death receptor-mediated therapies, histone deacetylase inhibition, immunotherapeutics, and oncolytics.

Gray A, Aronson WJ, Barnard RJ, et al.
Global Igfbp1 deletion does not affect prostate cancer development in a c-Myc transgenic mouse model.
J Endocrinol. 2011; 211(3):297-304 [PubMed] Free Access to Full Article Related Publications
Circulating insulin-like growth factor binding protein 1 (IGFBP1) levels vary in response to nutritional status, and pre-clinical studies suggest that elevated IGFBP1 may be protective against the development and progression of prostate cancer. We hypothesized that global deletion of Igfbp1 would accelerate the development of prostate cancer in a c-Myc transgenic mouse model. To test our hypothesis, c-Myc transgenic mice (Myc/BP-1 wild-type (WT)) were crossed and interbred with the Igfbp1 knockout mice (Myc/BP-1 KO). The animals were placed on a high-protein diet at weaning, weighed every 2 weeks, and euthanized at 16 weeks of age. Prostate histopathology was assessed and proliferation status was determined by Ki-67 and proliferating cell nuclear antigen analyses. IGF-related serum biomarkers and body composition were measured. No significant difference in the incidence of prostate cancer was observed between the Myc/BP-1 KO and the Myc/BP-1 WT mice (65 and 80% respectively, P=0.48). Proliferation was significantly decreased by 71% in prostate tissue of Myc/BP-1 KO mice compared with Myc/BP-1 WT mice. Myc/BP-1 KO mice exhibited a significant 6.7% increase in body weight relative to the Myc/BP-1 WT mice that was attributed to an increase in fat mass. Fasting insulin levels were higher in the Myc/BP-1 KO mice without any difference between the groups in fasting glucose concentrations. Thus, contrary to our hypothesis, global deletion of Igfbp1 in a c-Myc transgenic mouse model did not accelerate the development of prostate cancer. Global Igfbp1 deletion did result in a significant increase in body weight and body fat mass. Further studies are required to understand the underlying mechanisms for these metabolic effects.

Dong X, Li Y, Tang H, et al.
Insulin-like growth factor axis gene polymorphisms modify risk of pancreatic cancer.
Cancer Epidemiol. 2012; 36(2):206-11 [PubMed] Related Publications
OBJECTIVE: Insulin-like growth factor (IGF)-axis genes plays a critical role in cancer development and progression via their impact on the RAS/MAPK/ERK and PI3K/AKT/mTOR signaling pathways. We hypothesized that IGF-axis genetic variants modify individual susceptibility to pancreatic cancer.
METHODS: We retrospectively genotyped 41 single-nucleotide polymorphisms of 10 IGF-axis genes (IGF1, IGF2, IGF1R, IGF2R, IGFBP1, IGFBP3, IGFBP5, IRS1, IRS2, and IRS4) in 706 pancreatic cancer patients and 706 cancer-free controls using Sequenom and TaqMan technology. The association between genotype and pancreatic cancer risk was evaluated using multivariate logistic regression. A P value ≤.007 at a false discovery rate of 10% was set as the significance level.
RESULTS: We observed that the IGF1 *10212C>A and Ex4+2776G>A and IGF1R IVS2-70184A>G and IVS2+46329T>C variant genotypes were significantly associated with decreased pancreatic cancer risk (odds ratio [OR] range, 0.60-0.75) and that IGFBP1 Ex4+111A>G (I253M) was significantly associated with increased pancreatic cancer risk (OR=1.46) after adjusted for other risk factors and multiple comparisons (P≤.007). IGF2R and IGFBP3 variant haplotypes were associated with increased and decreased pancreatic cancer risk, respectively (P<.001). We also observed a weak interaction of the IGF1R IVS2+46329T>C and IGF2R Ex45+11C>T (L2222L) genotypes with diabetes (P(interaction)=.05) and interaction of IGF2R and IRS1 genotypes with alcohol consumption (P(interaction)=.03 and .019, respectively) on increased pancreatic cancer risk.
CONCLUSION: These findings support our hypothesis that polymorphic variants of IGF-axis genes act alone or jointly with other risk factors to affect susceptibility to pancreatic cancer.

Pearce CL, Doherty JA, Van Den Berg DJ, et al.
Genetic variation in insulin-like growth factor 2 may play a role in ovarian cancer risk.
Hum Mol Genet. 2011; 20(11):2263-72 [PubMed] Free Access to Full Article Related Publications
The insulin-like growth factor (IGF) signaling axis plays an important role in cancer biology. We hypothesized that genetic variation in this pathway may influence risk of ovarian cancer. A three-center study of non-Hispanic whites including 1880 control women, 1135 women with invasive epithelial ovarian cancer and 321 women with borderline epithelial ovarian tumors was carried out to test the association between tag single-nucleotide polymorphisms (tSNPs) (n=58) in this pathway and risk of ovarian cancer. We found no association between variation in IGF1, IGFBP1 or IGFBP3 and risk of invasive disease, whereas five tSNPs in IGF2 were associated with risk of invasive epithelial ovarian cancer at P<0.05 and followed-up one of the associated SNPs. We conducted genotyping in 3216 additional non-Hispanic white cases and 5382 additional controls and were able to independently replicate our initial findings. In the combined set of studies, rs4320932 was associated with a 13% decreased risk of ovarian cancer per copy of the minor allele carried (95% confidence interval 0.81-0.93, P-trend=7.4 × 10(-5)). No heterogeneity of effect across study centers was observed (p(het)=0.25). IGF2 is emerging as an important gene for ovarian cancer; additional genotyping is warranted to further confirm these associations with IGF2 and to narrow down the region harboring the causal SNP.

Rosendahl AH, Hietala M, Henningson M, et al.
IGFBP1 and IGFBP3 polymorphisms predict circulating IGFBP-3 levels among women from high-risk breast cancer families.
Breast Cancer Res Treat. 2011; 127(3):785-94 [PubMed] Related Publications
The insulin-like growth factor (IGF) pathway has been implicated as risk modifier in premenopausal breast cancer. In this study, associations between single nucleotide polymorphisms (SNPs) and diplotypes in the IGFBP1 and IGFBP3 genes and circulating IGFBP-3 levels, BRCA family status and breast cancer among women from high-risk breast cancer families were investigated. Nine IGFBP1 and IGFBP3 SNPs were genotyped with PCR-based methods in 323 women. Nine IGFBP1 and ten IGFBP3 diplotypes were identified. Plasma IGFBP-3 levels obtained during cycle day 18-23 were available for 231 women, 87 current users of combined oral contraceptives and 144 non-users. IGFBP1 (rs1995051 and rs4988515) and IGFBP3 (rs2471551 and rs2854744) SNPs were associated with circulating IGFBP-3 levels (P < 0.05). IGFBP1 (low) diplotypes were associated with lower IGFBP-3 levels and were more common in BRCA2 families OR 2.05 (95%CI 0.97-4.30). IGFBP3 (high) diplotypes were associated with higher IGFBP-3 levels and were more common in BRCAX families OR 1.68 (95%CI 1.04-2.74). After adjusting the models for BRCA family status, both the BRCA1 and BRCA2 family status (P ≤ 0.006) and the IGFBP1 diplotype GTAC/ACAT (P = 0.004) were associated with lower IGFBP-3 levels. Similarly, both the BRCA1 and BRCA2 family status (P ≤ 0.03) and the IGFBP-3 diplotypes GCA/GCG (P = 0.007) and GCG/CCG (P = 0.002) were significantly associated with lower IGFBP-3 levels, adjusted for age, weight, OC use, and other IGFBP diplotypes. No individual SNP was associated with breast cancer. There were 23 cases of breast cancer and one IGFBP1 diplotype was associated with a decreased risk of breast cancer after age 18 (log rank P=0.05). In conclusion, independent effects from IGFBP1, IGFBP3 diplotypes, and BRCA family status on IGFBP-3 levels were observed. These factors may influence the risk of breast cancer among women from high-risk breast cancer families.

Ranjzad F, Mahban A, Shemirani AI, et al.
Influence of gene variants related to calcium homeostasis on biochemical parameters of women with polycystic ovary syndrome.
J Assist Reprod Genet. 2011; 28(3):225-32 [PubMed] Free Access to Full Article Related Publications
PURPOSE: The purpose of this study was to evaluate the associations between polymorphisms in vitamin D receptor (VDR), parathyroid hormone (PTH), calcium sensing receptor (CASR), insulin receptor (INSR), and adiponectin (ADIPOQ) genes and biochemical characteristics of women with polycystic ovary syndrome (PCOS).
METHODS: Serum levels of LH, FSH, estradiol, testosterone, prolactin, SHBG, glucose, IGF-1, IGFBP-1, calcium, phosphorus, PTH, 25(OH)D, and 1,25(OH)(2) D were measured in 56 women with PCOS. Furthermore, genotyping five, one, one, two, and two polymorphisms of the VDR, PTH, CASR, INSR, and ADIPOQ genes, respectively, were performed.
RESULTS: The VDR TaqI "CC" genotype was associated with elevated serum levels of LH (p = 0.011). There were significant associations between decreased levels of SHBG and both VDR BsmI "GG" (p = 0.009) and ADIPOQ BsmI "CC" (p = 0.016) genotypes. Furthermore, patients with CaSR Hin1I "TG" genotype showed higher HoMA-IR (p = 0.008). All these associations remained significant after Bonferroni correction. In addition, phosphorus correlated negatively with estradiol (r =  -0.298, P = 0.026) and positively with glucose (r = 0.287, P = 0.032).
CONCLUSIONS: These data indicated for the first time that it is possible that the VDR and CASR gene variants through their effects on LH and SHBG levels, and insulin resistance are involved in pathogenesis of PCOS.

McGrath M, Lee IM, Buring J, De Vivo I
Common genetic variation within IGFI, IGFII, IGFBP-1, and IGFBP-3 and endometrial cancer risk.
Gynecol Oncol. 2011; 120(2):174-8 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: The insulin-like growth factor (IGF) pathway plays a critical role in the growth and development of the uterus and is believed to function as a mediator of steroid hormone actions in the endometrium. The local expression of genes encoding IGFs and IGF-binding proteins (IGFBPs) is important in determining IGF bioactivity in the uterus. Genetic variation in key genes within the IGF pathway may influence the rate of cellular proliferation and differentiation in the uterus and ultimately affect the risk of endometrial cancer. Our hypothesis is that variant alleles in key genes involved in the IGF pathway will influence the development of endometrial cancer.
METHODS: We conducted a case-control study nested within the Nurses' Health Study (NHS) and the Women's Health Study (WHS) to investigate the association between forty-four polymorphisms within IGFI, IGFII, IGFBP-1, and IGFBP-3 with endometrial cancer risk using 692 invasive endometrial cancer cases and 1723 matched controls. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to assess the risk of endometrial cancer.
RESULTS: We observed an inverse association with IGFII rs3741211 and endometrial cancer risk (OR=0.79 (95% CI: 0.63, 0.99)) and IGFII rs1004446 and endometrial cancer risk (OR=0.80 (95% CI: 0.68, 0.94)). We also observed an inverse association with IGFBP-3 rs2453839 and endometrial cancer risk (OR=0.81 (95%CI: 0.67, 0.98). However, we did not observe any statistically significant associations with the polymorphisms in IGFI and IGFBP1 and endometrial cancer risk.
CONCLUSIONS: Genetic variation with IGFII and IGFBP-3 may influence endometrial cancer risk in Caucasians. Polymorphisms in IGFI and IGFBP-1 were not associated with endometrial cancer risk, but further research is needed.

Schumacher FR, Cheng I, Freedman ML, et al.
A comprehensive analysis of common IGF1, IGFBP1 and IGFBP3 genetic variation with prospective IGF-I and IGFBP-3 blood levels and prostate cancer risk among Caucasians.
Hum Mol Genet. 2010; 19(15):3089-101 [PubMed] Free Access to Full Article Related Publications
The insulin-like growth factor (IGF) pathway has been implicated in prostate development and carcinogenesis. We conducted a comprehensive analysis, utilizing a resequencing and tagging single-nucleotide polymorphism (SNP) approach, between common genetic variation in the IGF1, IGF binding protein (BP) 1, and IGFBP3 genes with IGF-I and IGFBP-3 blood levels, and prostate cancer (PCa) risk, among Caucasians in the NCI Breast and Prostate Cancer Cohort Consortium. We genotyped 14 IGF1 SNPs and 16 IGFBP1/IGFBP3 SNPs to capture common [minor allele frequency (MAF) >or= 5%] variation among Caucasians. For each SNP, we assessed the geometric mean difference in IGF blood levels (N = 5684) across genotypes and the association with PCa risk (6012 PCa cases/6641 controls). We present two-sided statistical tests and correct for multiple comparisons. A non-synonymous IGFBP3 SNP in exon 1, rs2854746 (Gly32Ala), was associated with IGFBP-3 blood levels (P(adj) = 8.8 x 10(-43)) after adjusting for the previously established IGFBP3 promoter polymorphism A-202C (rs2854744); IGFBP-3 blood levels were 6.3% higher for each minor allele. For IGF1 SNP rs4764695, the risk estimates among heterozygotes was 1.01 (99% CI: 0.90-1.14) and 1.20 (99% CI: 1.06-1.37) for variant homozygotes with overall PCa risk. The corrected allelic P-value was 8.7 x 10(-3). IGF-I levels were significantly associated with PCa risk (P(trend) = 0.02) with a 21% increase of PCa risk when compared with the highest quartile to the lowest quartile. We have identified SNPs significantly associated with IGFBP-3 blood levels, but none of these alter PCa risk; however, a novel IGF1 SNP, not associated with IGF-I blood levels, shows preliminary evidence for association with PCa risk among Caucasians.

Taverne CW, Verheus M, McKay JD, et al.
Common genetic variation of insulin-like growth factor-binding protein 1 (IGFBP-1), IGFBP-3, and acid labile subunit in relation to serum IGF-I levels and mammographic density.
Breast Cancer Res Treat. 2010; 123(3):843-55 [PubMed] Related Publications
Mammographic density is strongly related to increased breast cancer risk. Accumulating evidence indicates that a role for the IGF-pathway in mammographic density and breast cancer development. Here, we investigate whether common genetic variation in this pathway influences insulin-like growth factor-I (IGF-I) levels and mammographic density. In 1,916 premenopausal women within the Prospect-EPIC cohort, we examined associations of 14 haplotype tagging SNPs in the ALS, IGFBP1, and IGFBP3 genes with IGF-I circulating levels and mammographic density. In 657 women, who became postmenopausal during follow-up, we investigated how these SNPs were related with the decrease in density over menopause. Linear regression models were used for statistical analysis. None of the ALS or IGFBP3 SNPs were statistically significantly associated with IGF-I levels or mammographic density. The CC genotype for rs1908751 (IGFBP1) was associated with lower levels of IGF-I (110.9 ng/ml) compared to the CT/TT genotypes (115.7 ng/ml) (P = 0.04). Women with the CC genotype also had lower percent density, although not statistically significantly (P = 0.12). Women carrying the AA genotype for rs1995051 (IGFBP1) showed that borderline significantly lower IGF-I levels (P = 0.06) and significantly lower mammographic density (40.3% compared to 43.5% in the GG/GA genotypes; P = 0.05). No relationships were found for any of the SNPs in relation with changes in breast density over menopause. These findings suggest that common genetic variation in the IGFBP1 gene is weakly related to IGF-I levels and mammographic density. Our results do not provide support for such a role of genetic variants in the IGFBP3 and ALS genes.

van der Meer DL, Degenhardt T, Väisänen S, et al.
Profiling of promoter occupancy by PPARalpha in human hepatoma cells via ChIP-chip analysis.
Nucleic Acids Res. 2010; 38(9):2839-50 [PubMed] Free Access to Full Article Related Publications
The transcription factor peroxisome proliferator-activated receptor alpha (PPARalpha) is an important regulator of hepatic lipid metabolism. While PPARalpha is known to activate transcription of numerous genes, no comprehensive picture of PPARalpha binding to endogenous genes has yet been reported. To fill this gap, we performed Chromatin immunoprecipitation (ChIP)-chip in combination with transcriptional profiling on HepG2 human hepatoma cells treated with the PPARalpha agonist GW7647. We found that GW7647 increased PPARalpha binding to 4220 binding regions. GW7647-induced binding regions showed a bias around the transcription start site and most contained a predicted PPAR binding motif. Several genes known to be regulated by PPARalpha, such as ACOX1, SULT2A1, ACADL, CD36, IGFBP1 and G0S2, showed GW7647-induced PPARalpha binding to their promoter. A GW7647-induced PPARalpha-binding region was also assigned to SREBP-targets HMGCS1, HMGCR, FDFT1, SC4MOL, and LPIN1, expression of which was induced by GW7647, suggesting cross-talk between PPARalpha and SREBP signaling. Our data furthermore demonstrate interaction between PPARalpha and STAT transcription factors in PPARalpha-mediated transcriptional repression, and suggest interaction between PPARalpha and TBP, and PPARalpha and C/EBPalpha in PPARalpha-mediated transcriptional activation. Overall, our analysis leads to important new insights into the mechanisms and impact of transcriptional regulation by PPARalpha in human liver and highlight the importance of cross-talk with other transcription factors.

Verheus M, Maskarinec G, Woolcott CG, et al.
IGF1, IGFBP1, and IGFBP3 genes and mammographic density: the Multiethnic Cohort.
Int J Cancer. 2010; 127(5):1115-23 [PubMed] Free Access to Full Article Related Publications
Insulin-like growth factor-I (IGF-I) has mitogenic properties and stimulates cell growth. In this analysis, we investigated the relation between common genetic variation in IGF1, IGFBP1, and IGFBP3, and mammographic density among 819 women of Hawaiian, European, and Japanese ancestry from the Multiethnic Cohort Study. Mammographic density was assessed using a quantitative computer-assisted method. Previously identified tag single nucleotide polymorphisms (SNPs) for IGF1 (26 tag SNPs) and IGFBP1/IGFBP3 (22 tag SNPs) were genotyped among the 819 women. Mixed models were conducted to evaluate the associations between genetic variation and mammographic density. Two SNPs were borderline statistical significantly associated with mammographic density: rs35539615 on IGFBP1 (p = 0.05) and rs2453839 on IGFBP3 (p = 0.01). Rs35767on IGF1 (p = 0.03) was also associated with mammographic density, although in opposite direction of what was expected from previous findings with IGF-I levels. The majority of SNPs were, however, not associated with mammographic density. Analyses stratified by ethnicity showed similar results as the overall analyses for IGF1 and IGFBP1. However, for 4 SNPs in the IGFBP3 gene, the minor allele was associated with lower mammographic density in Japanese Americans and higher mammographic density in Caucasians. Given the large number of SNPs tested and the few borderline significant results, we only found weak evidence that genetic variations in IGFBP1 or IGFBP3 may be related to mammographic density. Ethnicity may modify these relations.

Terry KL, Tworoger SS, Gates MA, et al.
Common genetic variation in IGF1, IGFBP1 and IGFBP3 and ovarian cancer risk.
Carcinogenesis. 2009; 30(12):2042-6 [PubMed] Free Access to Full Article Related Publications
Insulin-like growth factor (IGF) 1 and its binding proteins foster cellular proliferation and inhibit apoptosis. In vitro studies show that IGF1 increases ovarian cell growth and invasive potential, suggesting a role for the IGF1 pathway in ovarian cancer etiology. We evaluated genetic variation in the IGF1, IGFBP1 and IGFBP3 genes in relation to ovarian cancer risk by genotyping 29 haplotype-tagging single nucleotide polymorphisms in 1173 cases and 1201 controls from the New England Case-Control (NECC) study and 296 cases and 854 controls from the Nurses' Health Study (NHS). The association of haplotypes and single nucleotide polymorphisms (SNPs) with ovarian cancer was estimated using unconditional (NECC) and conditional (NHS) logistic regression. Additionally, we evaluated the association of SNPs with IGF1, IGF-binding protein (IGFBP) 3 and IGFBP2 plasma levels (n = 380 NHS controls). Our data suggest a decreased risk for women carrying haplotype 2C of the IGF1 gene [odds ratios (ORs) = 0.82, 95% confidence intervals (CIs) = 0.69-0.98] and an increased risk for women carrying haplotype 1D (OR = 1.41, 95% CI = 1.03-1.94) or 2D (OR = 1.20, 95% CI = 1.01-1.41) in the binding proteins. When evaluated individually, three SNPs in the IGFBPs (rs10228265, rs4988515 and rs2270628) were associated with increased ovarian cancer risk, and several IGF1 (rs11111285, rs1996656 and rs1019731) and IGFBP3 (rs2270628, rs2854746 and rs2854744) SNPs were significantly associated with IGF1, IGFBP3 and IGFBP2 plasma levels. Some haplotypes and SNPs in the IGF pathway genes may be associated with ovarian cancer risk; however, these results need to be confirmed. Of particular interest was the IGFBP3 SNP rs2270628, which was associated with both increased IGF1 plasma levels and higher ovarian cancer risk.

Neuhausen SL, Brummel S, Ding YC, et al.
Genetic variation in insulin-like growth factor signaling genes and breast cancer risk among BRCA1 and BRCA2 carriers.
Breast Cancer Res. 2009; 11(5):R76 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Women who carry mutations in BRCA1 and BRCA2 have a substantially increased risk of developing breast cancer as compared with the general population. However, risk estimates range from 20 to 80%, suggesting the presence of genetic and/or environmental risk modifiers. Based on extensive in vivo and in vitro studies, one important pathway for breast cancer pathogenesis may be the insulin-like growth factor (IGF) signaling pathway, which regulates both cellular proliferation and apoptosis. BRCA1 has been shown to directly interact with IGF signaling such that variants in this pathway may modify risk of cancer in women carrying BRCA mutations. In this study, we investigate the association of variants in genes involved in IGF signaling and risk of breast cancer in women who carry deleterious BRCA1 and BRCA2 mutations.
METHODS: A cohort of 1,665 adult, female mutation carriers, including 1,122 BRCA1 carriers (433 cases) and 543 BRCA2 carriers (238 cases) were genotyped for SNPs in IGF1, IGF1 receptor (IGF1R), IGF1 binding protein (IGFBP1, IGFBP2, IGFBP5), and IGF receptor substrate 1 (IRS1). Cox proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was assumed; and for single SNP analyses, no additivity assumptions were made.
RESULTS: Among BRCA1 carriers, significant associations were found between risk of breast cancer and LD blocks in IGF1R (global P = 0.011 for LD block 2 and global P = 0.012 for LD block 11). Among BRCA2 carriers, an LD block in IGFBP2 (global P = 0.0145) was found to be associated with the time to breast cancer diagnosis. No significant LD block associations were found for the other investigated genes among BRCA1 and BRCA2 carriers.
CONCLUSIONS: This is the first study to investigate the role of genetic variation in IGF signaling and breast cancer risk in women carrying deleterious mutations in BRCA1 and BRCA2. We identified significant associations in variants in IGF1R and IRS1 in BRCA1 carriers and in IGFBP2 in BRCA2 carriers. Although there is known to be interaction of BRCA1 and IGF signaling, further replication and identification of causal mechanisms are needed to better understand these associations.

Mavropoulos JC, Buschemeyer WC, Tewari AK, et al.
The effects of varying dietary carbohydrate and fat content on survival in a murine LNCaP prostate cancer xenograft model.
Cancer Prev Res (Phila). 2009; 2(6):557-65 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Numerous dietary factors elevate serum levels of insulin and insulin-like growth factor I (IGF-I), both potent prostate cancer mitogens. We tested whether varying dietary carbohydrate and fat, without energy restriction relative to comparison diets, would slow tumor growth and reduce serum insulin, IGF-I, and other molecular mediators of prostate cancer in a xenograft model.
EXPERIMENTAL DESIGN: Individually caged male severe combined immunodeficient mice (n = 130) were randomly assigned to one of three diets (described as percent total calories): very high-fat/no-carbohydrate ketogenic diet (NCKD: 83% fat, 0% carbohydrate, 17% protein), low-fat/high-carbohydrate diet (LFD: 12% fat, 71% carbohydrate, 17% protein), or high-fat/moderate-carbohydrate diet (MCD: 40% fat, 43% carbohydrate, 17% protein). Mice were fed to maintain similar average body weights among groups. Following a preliminary feeding period, mice were injected with 1 x 10(6) LNCaP cells (day 0) and sacrificed when tumors were >or=1,000 mm(3).
RESULTS: Two days before tumor injection, median NCKD body weight was 2.4 g (10%) and 2.1 g (8%) greater than the LFD and MCD groups, respectively (P < 0.0001). Diet was significantly associated with overall survival (log-rank P = 0.004). Relative to MCD, survival was significantly prolonged for the LFD (hazard ratio, 0.49; 95% confidence interval, 0.29-0.79; P = 0.004) and NCKD groups (hazard ratio, 0.59; 95% confidence interval, 0.37-0.93; P = 0.02). Median serum insulin, IGF-I, IGF-I/IGF binding protein-1 ratio, and IGF-I/IGF binding protein-3 ratio were significantly reduced in NCKD relative to MCD mice. Phospho-AKT/total AKT ratio and pathways associated with antiapoptosis, inflammation, insulin resistance, and obesity were also significantly reduced in NCKD relative to MCD tumors.
CONCLUSIONS: These results support further preclinical exploration of carbohydrate restriction in prostate cancer and possibly warrant pilot or feasibility testing in humans.

Johansson M, McKay JD, Rinaldi S, et al.
Genetic and plasma variation of insulin-like growth factor binding proteins in relation to prostate cancer incidence and survival.
Prostate. 2009; 69(12):1281-91 [PubMed] Related Publications
BACKGROUND: Binding proteins regulate bioavailability of insulin-like growth factor-I (IGF-I) in the circulation and affect apoptosis of tumor cells in the prostate. We analyzed genetic variation within genes coding for IGF binding proteins in relation to prostate cancer incidence and survival. We also investigated if circulating IGFBP3 affects prostate cancer-specific survival.
MATERIALS AND METHODS: Eleven haplotype tagging SNPs and two single SNPs in the IGFBP1, IGFBP3, and IGFALS genes were genotyped within the CAncer Prostate in Sweden (CAPS) study including 2,774 cases and 1,736 controls. Plasma samples for analyses of total- and intact IGFBP3 levels were available for 1,521 cases and 909 controls. Complete follow-up of vital status was achieved by linkage to the Swedish Cause of Death Register.
RESULTS: We found no clear association between the genetic variants and prostate cancer incidence or survival. The rare allele of the IGFBP3 SNP rs2854744 was associated with elevated plasma levels of total IGFBP3 (P(trend) = 9 x 10(-8)), but not intact IGFBP3 (P(trend) = 0.16). Elevated levels of total- (P(trend) = 0.03) and intact IGFBP3 (P(trend) = 6 x 10(-14)) were associated with increased risk of prostate cancer specific death. Treatment and tumor characteristics accounted for the association with total IGFBP3, whereas the association with intact IGFBP3 was attenuated, but still statistically significant in adjusted analysis (P(trend-adjusted) = 0.0004). Elevated intact IGFBP3 was also significantly associated with increased risk of prostate cancer-specific death among patients who were chemically or surgically castrated (P(trend-adjusted) = 0.0003), and among patients who had not been treated (P(trend-adjusted) = 0.02).
CONCLUSIONS: Circulating levels of intact IGFBP3 measured after diagnosis is associated with increased risk of prostate cancer-specific death.

Stockwin LH, Vistica DT, Kenney S, et al.
Gene expression profiling of alveolar soft-part sarcoma (ASPS).
BMC Cancer. 2009; 9:22 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Alveolar soft-part sarcoma (ASPS) is an extremely rare, highly vascular soft tissue sarcoma affecting predominantly adolescents and young adults. In an attempt to gain insight into the pathobiology of this enigmatic tumor, we performed the first genome-wide gene expression profiling study.
METHODS: For seven patients with confirmed primary or metastatic ASPS, RNA samples were isolated immediately following surgery, reverse transcribed to cDNA and each sample hybridized to duplicate high-density human U133 plus 2.0 microarrays. Array data was then analyzed relative to arrays hybridized to universal RNA to generate an unbiased transcriptome. Subsequent gene ontology analysis was used to identify transcripts with therapeutic or diagnostic potential. A subset of the most interesting genes was then validated using quantitative RT-PCR and immunohistochemistry.
RESULTS: Analysis of patient array data versus universal RNA identified elevated expression of transcripts related to angiogenesis (ANGPTL2, HIF-1 alpha, MDK, c-MET, VEGF, TIMP-2), cell proliferation (PRL, IGFBP1, NTSR2, PCSK1), metastasis (ADAM9, ECM1, POSTN) and steroid biosynthesis (CYP17A1 and STS). A number of muscle-restricted transcripts (ITGB1BP3/MIBP, MYF5, MYF6 and TRIM63) were also identified, strengthening the case for a muscle cell progenitor as the origin of disease. Transcript differentials were validated using real-time PCR and subsequent immunohistochemical analysis confirmed protein expression for several of the most interesting changes (MDK, c-MET, VEGF, POSTN, CYP17A1, ITGB1BP3/MIBP and TRIM63).
CONCLUSION: Results from this first comprehensive study of ASPS gene expression identifies several targets involved in angiogenesis, metastasis and myogenic differentiation. These efforts represent the first step towards defining the cellular origin, pathogenesis and effective treatment strategies for this atypical malignancy.

Patel AV, Cheng I, Canzian F, et al.
IGF-1, IGFBP-1, and IGFBP-3 polymorphisms predict circulating IGF levels but not breast cancer risk: findings from the Breast and Prostate Cancer Cohort Consortium (BPC3).
PLoS One. 2008; 3(7):e2578 [PubMed] Free Access to Full Article Related Publications
IGF-1 has been shown to promote proliferation of normal epithelial breast cells, and the IGF pathway has also been linked to mammary carcinogenesis in animal models. We comprehensively examined the association between common genetic variation in the IGF1, IGFBP1, and IGFBP3 genes in relation to circulating IGF-I and IGFBP-3 levels and breast cancer risk within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). This analysis included 6,912 breast cancer cases and 8,891 matched controls (n = 6,410 for circulating IGF-I and 6,275 for circulating IGFBP-3 analyses) comprised primarily of Caucasian women drawn from six large cohorts. Linkage disequilibrium and haplotype patterns were characterized in the regions surrounding IGF1 and the genes coding for two of its binding proteins, IGFBP1 and IGFBP3. In total, thirty haplotype-tagging single nucleotide polymorphisms (htSNP) were selected to provide high coverage of common haplotypes; the haplotype structure was defined across four haplotype blocks for IGF1 and three for IGFBP1 and IGFBP3. Specific IGF1 SNPs individually accounted for up to 5% change in circulating IGF-I levels and individual IGFBP3 SNPs were associated up to 12% change in circulating IGFBP-3 levels, but no associations were observed between these polymorphisms and breast cancer risk. Logistic regression analyses found no associations between breast cancer and any htSNPs or haplotypes in IGF1, IGFBP1, or IGFBP3. No effect modification was observed in analyses stratified by menopausal status, family history of breast cancer, body mass index, or postmenopausal hormone therapy, or for analyses stratified by stage at diagnosis or hormone receptor status. In summary, the impact of genetic variation in IGF1 and IGFBP3 on circulating IGF levels does not appear to substantially influence breast cancer risk substantially among primarily Caucasian postmenopausal women.

Chahal J, Chen CC, Rane MJ, et al.
Regulation of insulin-response element binding protein-1 in obesity and diabetes: potential role in impaired insulin-induced gene transcription.
Endocrinology. 2008; 149(10):4829-36 [PubMed] Free Access to Full Article Related Publications
One of the major mechanisms by which insulin modulates glucose homeostasis is through regulation of gene expression. Therefore, reduced expression of transcription factors that are required for insulin-regulated gene expression may contribute to insulin resistance. We recently identified insulin response element-binding protein-1 (IRE-BP1) as a transcription factor that binds and transactivates multiple insulin-responsive genes, but the regulation of IRE-BP1 in vivo is largely unknown. In this study, we show that IRE-BP1 interacts with the insulin response sequence of the IGF-I, IGFBP-1, and IGFBP-3 genes using chromatin immunoprecipitation assay. Furthermore, activation by IRE-BP1 is sequence specific and mimics that of the insulin effect on gene transcription. Tissue expression of IRE-BP1 is 50- to 200-fold higher in classical insulin target compared with nontarget tissues in lean animals, with a significantly reduced level of expression in the skeletal muscle and adipose tissue in obese and diabetic animals. In the liver, IRE-BP1 is localized to the nucleus in lean rats but is sequestered to the cytoplasm in obese and diabetic animals. Cytoplasmic sequestration appears to be related to inhibition of insulin-mediated phosphatidylinositol-3 kinase signaling. Therefore, in diabetes and obesity, the mechanisms involved in reducing the transactivation of the insulin response sequence by IRE-BP1 include decreased gene transcription and nuclear exclusion to prevent DNA binding. Our study supports the notion that IRE-BP1 may be relevant to the action of insulin in vivo and may play a role in the development of insulin resistance and diabetes.

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.

Thakur A, Bollig A, Wu J, Liao DJ
Gene expression profiles in primary pancreatic tumors and metastatic lesions of Ela-c-myc transgenic mice.
Mol Cancer. 2008; 7:11 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Pancreatic carcinoma usually is a fatal disease with no cure, mainly due to its invasion and metastasis prior to diagnosis. We analyzed the gene expression profiles of paired primary pancreatic tumors and metastatic lesions from Ela-c-myc transgenic mice in order to identify genes that may be involved in the pancreatic cancer progression. Differentially expressed selected genes were verified by semi-quantitative and quantitative RT-PCR. To further evaluate the relevance of some of the selected differentially expressed genes, we investigated their expression pattern in human pancreatic cancer cell lines with high and low metastatic potentials.
RESULTS: Data indicate that genes involved in posttranscriptional regulation were a major functional category of upregulated genes in both primary pancreatic tumors (PT) and liver metastatic lesions (LM) compared to normal pancreas (NP). In particular, differential expression for splicing factors, RNA binding/pre-mRNA processing factors and spliceosome related genes were observed, indicating that RNA processing and editing related events may play critical roles in pancreatic tumor development and progression. High expression of insulin growth factor binding protein-1 (Igfbp1) and Serine proteinase inhibitor A1 (Serpina1), and low levels or absence of Wt1 gene expression were exclusive to liver metastatic lesion samples.
CONCLUSION: We identified Igfbp1, Serpina1 and Wt1 genes that are likely to be clinically useful biomarkers for prognostic or therapeutic purposes in metastatic pancreatic cancer, particularly in pancreatic cancer where c-Myc is overexpressed.

Li ZQ, Yu WP, Xie XD, et al.
Association of gastric cancer with tyrosine hydroxylase gene polymorphism in a northwestern Chinese population.
Clin Exp Med. 2007; 7(3):98-101 [PubMed] Related Publications
Gastric cancer (GC) is a common and complex disease caused by multifactors. The aim of our study was to investigate the association of the common polymorphisms detected in insulin-like growth factor (IGF)-II, IGF-1 receptor, insulin-like growth factor binding protein 1 (IGFBP1), insulin (INS) and tyrosine hydroxylase (TH) with susceptibility to GC in a northwestern Chinese population. One hundred and fifty-four GC patients and 166 healthy controls were investigated in our study. The genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. The frequencies of CC and CT genotypes of TH were significantly higher in GC patients than in controls, as the odds ratios were 3.03 (95%CI 1.438-6.362, P=0.003) and 1.97 (95%CI 1.218-3.167, P=0.005), respectively. No association was found between the polymorphisms of IGF-II ApaI, insulin-like growth factor-1 receptor MnlI, IGFBP1 Bgl II and INS-23HphI and the development of GC. The presence of CC and CT genotypes of TH was associated with a significantly increased risk of GC. But the polymorphisms of other genes detected did not indicate an increased risk of GC in the investigated population.

Hoyo C, Grubber J, Demark-Wahnefried W, et al.
Grade-specific prostate cancer associations of IGF1 (CA)19 repeats and IGFBP3-202A/C in blacks and whites.
J Natl Med Assoc. 2007; 99(7):718-22 [PubMed] Free Access to Full Article Related Publications
Carrying the cytosine-adenosine (CA)19 repeat polymorphism in insulin-like growth factor-1 (IGF1) is associated with lower serum proteins and decreased prostate cancer risk. Carrying the -202A/C genotype in insulin-like growth factor binding protein-3 (IGFBP3) also has been associated with lower serum levels of the binding protein. However, the association between this variant and prostate cancer is inconsistent. To test the hypothesis that inconsistencies are partly due to cancer grade-specific differences in strength and direction of associations, we reanalyzed data from our previous Durham Veterans Administration Hospital study of blacks and whites comprising 47 cases (19 African Americans) with Gleason sum > or = 7, 50 cases (30 African Americans) with Gleason sum < 7 and 93 controls (49 African Americans). Compared to controls, the association between carrying the IGFBP3 C allele and prostate cancer risk was in OR(Low-Gleason) = 4.0; 95% CI: 1.4-12.3 compared to OR(High-Gleason) = 1.0; 95% CI: 0.4-2.2. Association patterns were similar in African Americans (OR(Low-Gleason) = 3.6; 95% CI: 1.0-13.2 vs. OR(High-Gleason) = 1.4; 95% CI: 0.4-2.3) and whites (OR(Low-Gleason) = 5.6; 95% CI: 0.6-49.0 vs. OR(High-Gleason) = 0.6; 95% CI: 0.2-2.2). The inverse association between carrying the IGF1 (CA)19 repeat variant did not vary by grade or ethnicity. If confirmed in larger studies, these findings support the hypothesis that the association between IGFBP3 C allele and prostate cancer is grade specific in both ethnic groups.

Magne L, Blanc E, Marchand A, et al.
Stabilization of IGFBP-1 mRNA by ethanol in hepatoma cells involves the JNK pathway.
J Hepatol. 2007; 47(5):691-8 [PubMed] Related Publications
BACKGROUND/AIMS: Insulin-like growth factor-binding protein-1 (IGFBP-1) modulates cell growth and metabolism in a variety of physiopathological conditions. The aim of this study was to determine the molecular mechanisms involved in IGFBP-1 upregulation by ethanol.
METHODS: We studied IGFBP-1 regulation by ethanol at the protein, mRNA and gene promoter levels in the human hepatocarcinoma cell line, HepG2, which does not express significantly ethanol-metabolizing enzymes.
RESULTS: Ethanol (35-150mM) induced the IGFBP-1 mRNA and protein up to 5-fold in a dose-dependent manner. A similar effect was observed using primary cultures of human hepatocytes. Various inhibitors of ethanol metabolism and the antioxidant N-acetylcysteine did not prevent ethanol effects. While ethanol did not modify the IGFBP-1 gene promoter activity, it elicited a 2- to 3-fold increase in IGFBP-1 mRNA half-life and this stabilization required the 5' and the 3' untranslated mRNA region. Ethanol triggered a rapid activation of c-Jun N-terminal Kinase (JNK) in HepG2 cells and IGFBP-1 induction was significantly decreased by a specific inhibitor of JNK.
CONCLUSIONS: This study reveals a novel pathway of gene regulation by alcohol which involves the activation of JNK and the consequent mRNA stabilization.

Smith P, Nicholson LJ, Syed N, et al.
Epigenetic inactivation implies independent functions for insulin-like growth factor binding protein (IGFBP)-related protein 1 and the related IGFBPL1 in inhibiting breast cancer phenotypes.
Clin Cancer Res. 2007; 13(14):4061-8 [PubMed] Related Publications
PURPOSE: To analyze epigenetic regulation of two related genes, insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) and IGFBPL1, and its significance as a determinant of clinical phenotypes in human breast cancer.
EXPERIMENTAL DESIGN: We have investigated the expression and epigenetic regulation of IGFBP-rP1 and IGFBPL1 in human breast cancer cell lines and primary and metastatic carcinomas.
RESULTS: Expression of IGFBP-rP1 and IGFBPL1 is down-regulated in breast cancer cell lines. Aberrant methylation in the CpG islands of each gene correlates well with loss of expression at the mRNA level. Analysis of methylation in DNA isolated from human primary breast tumors showed that methylation in either gene was associated with a worse overall survival (OS; P=0.008) and disease-free survival (DFS) following surgery (P=0.04) and worse DFS following adjuvant chemotherapy (P=0.01). Methylation of IGFBP-rP1 alone was associated with a trend toward decreased OS (P=0.10) and decreased DFS (P=0.25). Methylation in IGFBPL1 was clearly associated with worse OS (P=0.001) and DFS (P<0.0001). Methylation in either IGFBP-rP1 or IGFBPL1 was significantly associated with nodal disease (P<0.001).
CONCLUSIONS: Expression of IGFBP-rP1 and IGFBPL1 is regulated by aberrant hypermethylation in breast cancer, implying that inactivation of these genes is involved in the pathogenesis of this malignancy. Analysis of methylation of these genes may have utility in prediction of clinical phenotypes, such as nodal disease and response to chemotherapy.

Oishi Y, Ohnishi M, Kobayashi-Hattori K, et al.
Cadmium cation increases the production and mRNA levels of insulin-like growth factor-binding protein-1 in HepG2.
Biosci Biotechnol Biochem. 2007; 71(5):1334-7 [PubMed] Related Publications
The production of insulin-like growth factor-binding protein-1 (IGFBP-1) in HepG2 was increased by cadmium cation (Cd2+) at 3 microM, but not by other divalent cations. The mRNA level of IGFBP-1 was also increased by the administration of 3 microM of Cd(2+). These results suggest that Cd(2+) impacts the gene expression of IGFBP-1, which leads to production of IGFBP-1.

Sato Y, Chen Z, Miyazaki K
Strong suppression of tumor growth by insulin-like growth factor-binding protein-related protein 1/tumor-derived cell adhesion factor/mac25.
Cancer Sci. 2007; 98(7):1055-63 [PubMed] Related Publications
Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) has been shown to induce cellular senescence or apoptosis of breast and prostate cancer cell lines in vitro. To examine whether IGFBP-rP1 acts as a tumor-suppressive protein in vivo, we established two model systems. Expression of IGFBP-rP1 in the human bladder carcinoma cell line EJ-1 was blocked by RNA interference. Human colon cancer cell line DLD-1, which did not express endogenous IGFBP-rP1, was transfected with an IGFBP-rP1 expression vector. When injected intraperitoneally or subcutaneously into nude mice, the IGFBP-rP1-expressing EJ-1 and DLD-1 cell lines grew poorly, whereas the IGFBP-rP1 non-producers grew rapidly and produced large tumors. In monolayer culture the IGFBP-rP1 producers and non-producers grew similarly in each model, whereas in soft agar culture the former produced far less colonies than the latter. The IGFBP-rP1 producers had IGFBP-rP1 bound to the cell surface, and adhered more efficiently to fibronectin and laminin-5 than the respective non-producers. Expression of IGFBP-rP1 did not affect the efficiency of insulin signaling. These results demonstrate that IGFBP-rP1 strongly suppresses tumor growth by an insulin-independent or insulin-like growth factor-independent mechanism. Cell surface IGFBP-rP1 may reduce the anchorage-independent growth ability, leading to the marked loss of tumorigenicity.

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