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Original Studies |
Department of Pediatrics, Université de Montréal (C.D., F.W., J.P.); and Departments of Medicine and Oncology (M.P., F.R.) and Genome Center (B.G., T.H.), McGill University, Montréal, Québec, Canada H3T 1E2; and Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School (J.M., M.S.), Boston, Massachusetts 02115
Address all correspondence and requests for reprints to: Dr. Michael Pollak, Lady Davis Research Institute of McGill University and Jewish General Hospital, 3999 chemin de la Cote Sainte Catherine, Montréal, Québec, Canada H3T 1E2. E-mail: md49{at}musica.mcgill.ca
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Abstract |
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Direct sequencing of genomic DNA specimens from a multiethnic population identified several single nucleotide polymorphisms in the promoter region of IGFBP3. For the most common single nucleotide polymorphism (nucleotide -202) found to be in Hardy-Weinberg equilibrium, genotype was highly correlated to circulating level of IGFBP-3 in 478 men from the Physicians’ Health Study. In vitro, we documented significantly higher promoter activity of the A allele at the -202 locus compared with the C allele, consistent with the relationship observed between genotype and circulating IGFBP-3 (AA > AC > CC).
A positive correlation was observed between circulating retinol levels and circulating IGFBP-3 levels; subset analysis by genotype showed that this relationship was only present among individuals carrying an A allele at -202 (AA > AC > CC). Tall individuals or individuals with a body mass index of 27 or greater had levels of circulating IGFBP-3 that were significantly higher when they possessed at least one A allele (AA > AC > CC).
The IGFBP3 promoter region deserves investigation as a locus where polymorphic variation occurs frequently and may influence GH responsiveness, somatic growth, and possibly cancer risk.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The gene for IGFBP-3 (IGFBP3) is highly conserved among
species and is present as a single copy on chromosome 7p14-p12. GH and
insulin are two of the hormones important in IGFBP3
up-regulation (18), in addition to agents that induce
growth inhibition/apoptosis such as p53 (19), retinoic
acid (20, 21), vitamin D (22), antiestrogens
such as tamoxifen (23), antiandrogens (24),
transforming growth factor-ß (21, 25), and tumor
necrosis factor-
(26). There is evidence that this
up-regulation contributes to the antiproliferative actions of some of
the drugs used in chemoprevention (2, 20, 21, 23, 27). In
addition, the growth-promoting action of estrogens and ligands for the
epidermal growth factor receptor have been shown to down-regulate
IGFBP3 expression (18).
Twin studies (28) have shown that about half of the intraindividual variability in circulating IGFBP-3 levels is genetically determined, but specific loci involved have not been described. We therefore undertook studies to determine whether variability in IGFBP-3 levels might be related to polymorphic variants of the promoter region of the gene.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Approximately 1.5 kb of the promoter region of IGFBP3 (see below) was sequenced for each of 32 samples of genomic DNA from a multiethnic Montréal population to identify possible polymorphisms. We then genotyped these loci by direct sequencing in 40 leukocyte DNA specimens from subjects in the Physicians’ Health Study (29). IGF-I, IGF-II, and IGFBP-3 levels had previously been measured in corresponding plasma samples, using enzyme-linked immunosorbent assay methods (9). This pilot work suggested that a single nucleotide polymorphism at position -202 (nucleotides relative to the CAP site) was related to the circulating IGFBP-3 concentration, because mean IGFBP-3 levels were higher in subjects with the AA genotype than in those with the CC genotype (P < 0.05, by unpaired t test). To explore this possibility in more detail, we developed a restriction fragment length polymorphism (RFLP) assay and genotyped 524 subjects at the -202 locus (colon cancer cases matched to controls 1:2) from the Physicians’ Health Study. For 478 of these, we had previously (9) measured IGF-I, IGF-II, and IGFBP-3 plasma levels, height, and weight, and for 283 of these subjects, plasma retinol levels were also determined. All subjects gave informed consent for samples they provided to be used for scientific research.
IGFBP3 promoter polymorphism analysis
The following primer pairs were used to sequence IGFBP3 from -1500 to +19 relative to the CAP site (underlined portion corresponds to the M13 tail) in the initial screening of an ethnically mixed Montréal population: BP3Prom1F, 5'-GTTTTCCCAGTCACGACGTACAAGAG-GGAACGAAATTGATC-3'; BP3Prom1R, 5'-TTGTCTGCGCACCCC-CTCCTT-3' (Tm = 55 C); BP3Prom2F, 5'-GTTTTCCCAGTCACGAC-AGGAAAGTCTCCTCCCGCGGA-3'; BP3Prom2R, 5'-GCTCCTTAAG-GCAGGGCTTTTC-3' (Tm = 54 C); BP3Prom3F, 5'-GTTTTCCCA-GTCACGACGTACACGTTTCAGCAGTGCCCAGTTTA-3'; BP3Prom3R, 5'-TTCCGCTCTCGGGGTGAGGTCT-3' (Tm = 52 C); BP3Prom4F, 5'-GTTTTCCCAGTCACGACCCACGAGGTACACACGAATG-3'; and BP3Prom4R, 5'-AGCCGCAGTGCTCGCATCTGG-3' (Tm = 64 C).
Initial PCR conditions consisted of 25 ng genomic DNA, 1 U AmpliTaq Gold DNA Polymerase (Perkin-Elmer Corp., Mississaugua, Canada), 1 x PCR Gold Buffer (Perkin-Elmer Corp.), 1.5 mmol/L MgCl2, 0.2 mmol/L of each deoxy-NTP, and 2% dimethylsulfoxide in a total volume of 50 µL. After denaturation at 96 C for 10 min, 35 cycles were run with the following cycling parameters: 96 C for 30 s, Tm (see above) for 30 s, and 72 C for 1 min. The PCR reaction was purified on magnetic beads and then directly sequenced.
RFLP genotyping of the -202 single nucleotide polymorphism
A 50- to 250-ng aliquot of genomic DNA was mixed with PCR buffer, supplemented by 1.6 µmol/L of primers, 1 mmol/L MgCl2, 0.1 mmol/L of each deoxy-NTP, 2% dimethyl sulfoxide 2 U Taq DNA polymerase (Life Technologies, Inc., Burlington, Canada). Primer sense and antisense were 5'-CCA CGA GGT ACA CAC GAA TG-3' and 5'-AGC CGC AGT GCT CGC ATC TGG-3', respectively. The cycling parameters consisted of an initial incubation of 10 min at 94 C, followed by 35 cycles of 30 s at 96 C, 30 s at 64 C, and 1 min at 72 C. The reaction was terminated after a final extension of 5 min at 72 C. Twenty microliters of PCR product were digested with 5 U Alw21I (MBI Fermentas, Flamborough, Canada) from between 3–14 h at 37 C. Digestion products were visualized on a 2% agarose gel stained with ethidium bromide. Due to the presence of three Alw21I sites in the PCR product, one of which is destroyed when there is a C in position -202, band sizes were 242 and 162 bp (A allele), and 288 and 162 bp (C allele).
Promoter activity assay
PCR products for human IGFBP3 promoter (bp -441 to +91) (30) were obtained from samples with A or C at bp -202. PCR conditions were the same as described above, except for the addition of linkers with restriction sites in 28-mer primers. The sense primer containing a PstI site was 5'-AAC TGC AGC CAC GAG GTA CAC ACG AAT G-3', and the antisense primer containing an XbaI was 5'-GCT CTA GAC GCA GGG ATG GGG CGA CAG T-3'. To generate IGFBP3 reporter gene constructs for transient transfections, we cloned the two different 548-bp PCR products into the PstI/XbaI sites of pCAT-Basic plasmid (Promega Corp., Madison, WI). These constructs were termed pCAT BP3A and pCAT BP3C. As controls, we used the promoterless pCAT-Basic plasmid and the pCAT-control plasmid containing simian virus 40 promoter and enhancer. The authenticity and directionality of all of the constructs were verified by restriction enzyme analysis and were confirmed by sequencing both sense and antisense strands. IGFBP3-expressing human liver cancer SK-Hep-1 cells and MCF-7 breast cancer cells obtained from American Type Culture Collection (Manassas, VA) were used for transient transfections. Briefly, 1.5 x 105 MCF-7 cells or 3 x 105 SK-Hep-1 cells in 35-cm2 multiwell dishes in serum-free medium (Opti-MEM, Life Technologies, Inc.) were cotransfected with 2 µg of each chloramphenicol acetyltransferase (CAT) construct and with 0.7 µg pSVß (a plasmid encoding ß-galactosidase, Promega Corp.) using a cationic liposome formulation (lipofectin, Life Technologies, Inc.). The CAT and ß-galactosidase assays were then performed 48 h later as previously detailed (31).
Statistical analyses
We assessed the genotype distributions for significant departure
from the Hardy-Weinberg equilibrium using the
2 test. A general linear regression
model was employed to estimate the percent variation in IGFBP-3 that
can be explained by the -202 polymorphism alone or by the genotype and
age. Analysis of covariance was used to compare the age-adjusted levels
of IGFBP-3 according to the genotype or plasma retinol levels.
Age-adjusted mean levels were also obtained according to the genotype
and tertile of plasma retinol, quartile of height, or four groups of
body mass index among case subjects and control subjects. Unconditional
logistic regression was used to estimate the relative risks (RRs) and
95% confidence intervals (CIs) for association of the -202
polymorphism with the risk of colorectal cancer. The RRs were also
calculated adjusting for age, smoking, IGF-I, body mass index (BMI),
and alcohol intake. All P values are two-sided, and all
analyses used the SAS program package (SAS Institute, Inc., Cary, NC).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), and the genotype at one of these loci
(-202) appeared to be significantly related to the age-adjusted
circulating IGFBP-3 concentration. This locus is near elements believed
to direct basal promoter activity of IGFBP3 (18, 30) (Fig 1) and can be
conveniently genotyped by an RFLP assay (Fig 2).
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2 = 0.98;
P = 0.61).
As shown in Fig. 3, mean IGFBP-3 levels
were highest in the individuals with the AA genotype at the -202
IGFBP3 locus and declined significantly in a stepwise manner
in the presence of one or two copies of the C allele. The relationship
between genotype and circulating serum IGFBP-3 level was apparent with
or without adjustment for age. Using a general linear model, we
estimated that the percent variation in IGFBP-3 that can be
explained by the -202 polymorphism is 7.7% (r = 0.28); if both
polymorphism and subject age are included, 22.3% of the
interindividual variability in IGFBP-3 can be accounted for (r =
0.47). As anticipated, the -202 CC genotype was significantly
associated with the total circulating total IGF (IGF-I + IGF-II) level
in a dose-dependent fashion [AA vs. AC, 847 ± 15 and
792 ± 10 ng/mL, respectively (P = 0.002); AA
vs. CC, 847 ± 15 and 759 ± 13 ng/mL,
respectively (P = 0.0001)]. The -202 genotype was
also predictive of IGF-I/IGFBP-3 molar ratios (AA vs. CC,
0.211 ± 0.005 and 0.248 ± 0.004, respectively;
P < 0.0001) and IGF-II/IGFBP-3 molar ratios (AA
vs. CC, 1.018 ± 0.008 and 1.044 ± 0.007,
respectively; P = 0.02).
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Expression of IGFBP3 in vitro is known to be up-regulated by
retinoids (20, 21), but there have been no studies of
circulating IGFBP-3 levels in relation to circulating retinol levels.
Data for retinol levels, IGFBP-3 levels, and IGFBP3 -202
genotype were available for 283 subjects. Figure 4 summarizes the relationships among
these variables. Age-adjusted IGFBP-3 levels increased across tertiles
of plasma retinol (trend analysis: P < 0.005; Spearman
correlation coefficient r = 0.25; P < 0.001; Fig. 4A). When the age-adjusted mean levels of IGFBP-3 in each retinol
tertile were analyzed after stratification by genotype at the -202
locus, lower levels of IGFBP-3 were consistently observed with the CC
genotype regardless of retinol levels (Fig. 4B). Importantly, the
relationship of retinol level to IGFBP-3 level documented in Fig. 4A
was strongly dependent on genotype at the IGFBP3 -202
locus. Only the A allele, especially the AA genotype, was associated
with progressively higher levels of IGFBP-3 with increasing retinol
levels (overall IGFBP-3 level differed across retinol tertiles,
P = 0.001; within AA genotype, retinol tertile 1
vs. 2, P = 0.04; tertile 1 vs. 3,
P = 0.0001; within other genotypes, differences in
IGFBP-3 levels across retinol tertiles were not significant).
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and 3).
We noted that the AA genotype (associated with higher IGFBP-3 levels)
was overrepresented in shorter subjects (28% of subjects in the first
height quartile subjects were AA, vs. 20% of subjects in
the fourth height quartile; Table 3), whereas the CC genotype was more
prevalent among taller individuals (31% of subjects in the fourth
height quartile were CC, vs. 25% of subjects in the first
height quartile; Table 3), but these trends were of only borderline
significance (Ptrend = 0.05 and 0.04,
respectively). Overall, neither BMI nor height was related to the
age-adjusted circulating IGFBP-3 level. However, both height and BMI
influenced the relationship between the -202 IGFBP3
genotype and the circulating IGFBP-3 level. The polymorphism was less
significantly related to levels in shorter or leaner individuals than
in taller and larger subjects (Tables 2 and 3).
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shows the results of transient
transfection experiments, in which two IGFBP3 promoter
constructs that differed only at the -202 locus were cotransfected
with a ß-galactosidase-containing plasmid (to monitor transfection
efficiency). The activity of the reporter gene CAT in the transfectants
containing the BP3-C construct (normalized to ß-galactosidase
activity) was approximately half that of CAT activity in transfectants
containing the BP3-A construct. Similar results were obtained using
SK-Hep-1 and MCF-7 cells as transfection targets, providing in
vitro evidence that the -202 IGFBP3 polymorphism
influences promoter activity and, hence, expression of the gene.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our main finding is that the novel -202 polymorphism in the promoter region of IGFBP3 is related to the circulating IGFBP-3 level clinically and to the promoter activity of the gene in vitro. In vitro gene expression varied by approximately 50% between A- and C-containing alleles, whereas circulating levels varied according to genotype in the same direction, but to a lesser extent. This may reflect physiological compensatory mechanisms that serve to attenuate (but not abolish) the effect of differences in gene IGFBP-3 transcription on circulating IGFBP-3 levels.
Both height and BMI influenced the relationship between the -202 IGFBP3 genotype and the circulating IGFBP-3 level. The polymorphism was less related to levels in shorter or leaner individuals than in taller and larger subjects. These findings may relate to the fact that taller and larger individuals tend to have higher levels of GH and insulin, respectively, both of which have been reported to up-regulate IGFBP3 expression (18), assuming that the genotype at the -202 locus influences promoter responsivity to these regulators. Our observations suggest that it may be worthwhile to extend these studies to children, in whom measurement of circulating IGFBP-3 has been used to evaluate GH deficiency (32, 33), as well as in models designed to predict the efficacy of GH therapy (34, 35). A significant problem in either clinical context has been the large interindividual variability (14) of this analyte, and we hypothesize that the statistical relationship between circulating IGFBP-3 and GH status may be improved by subgrouping children according to genotype.
Although the circulating IGF-I concentration has recently been reported to be positively related to the risk of developing certain common epithelial cancers, high circulating IGFBP-3 levels appear to attenuate risk and/or to be inversely related to risk (7, 8, 9, 10, 11, 12). On the basis of experimental studies (36, 37), we had hypothesized that cell renewal kinetics are influenced by IGF bioactivity, which is related to IGFBP3 expression and hence to the -202 IGFBP3 polymorphism. The lack of a detectable association between genotype and colorectal cancer risk in our study population is not unexpected, given that the variation in circulating IGFBP-3 concentrations across quintiles of the controls in the study population is greater than the spread across genotypes (highest quintile mean IGFBP-3 = 3944 ng/mL; lowest quintile mean IGFBP-3 = 2161 ng/mL; mean IGFBP-3 for controls with AA genotype = 3274 ng/mL; mean IGFBP-3 for controls with CC genotype = 2753 ng/mL). We previously presented evidence that the RR for colorectal cancer of subjects in the highest quintile of circulating IGFBP-3 is 0.47 of that in subjects in the lowest (9). As we now calculate that 7.7% of the interindividual variability in circulating IGFBP-3 is attributable to the polymorphism, we would expect the RR related to the polymorphism to be small. Our sample size does not provide sufficient power to document small differences in relative risk or to detect a relationship between genotype and risk confined to subpopulations defined by either known modulators of IGFBP-3 levels or known colorectal cancer risk factors. The -202 IGFBP3 locus, therefore, deserves investigation not as a rare mutation associated with a large increase in cancer risk, but, rather, as a site of common polymorphic variation that may subtly influence cancer risk. It is important to recognize that disease burden attributable to common polymorphisms that weakly predispose is not necessarily less than the burden attributable to rare mutations that strongly predispose.
It will be of interest to study racial variation in allele frequency at the -202 IGFBP3 locus, as this may be related to recent observations that Afro-Americans, who have a higher risk and/or worse prognosis for both prostate cancer and breast cancer than Caucasians (38, 39), tend to have lower circulating IGFBP-3 levels (40, 41). We have determined that the -202 IGFBP3 polymorphism is related to the circulating IGFBP-3 level in young women as well as men (41A ).
The physiological basis for the positive relationship between circulating serum IGF-I level and cancer risk and the negative relationship between circulating IGFBP-3 level and cancer risk (7, 8, 9, 10, 11, 12, 42) requires further investigation. These variables are positively correlated with each other, as IGFBP-3 is the major carrier protein for IGFs and thus is a major determinant of circulating IGF levels, but is oppositely related to risk. We speculate that circulating levels may not be direct determinants of risk, but, rather, may serve as proxies for tissue expression of these proteins, and that the balance between IGFs and IGFBPs in the microenvironment of normal and/or partially transformed epithelial cell populations may influence renewal kinetics and thus the risk of developing a clinically detectable cancer. It will be of interest to determine whether circulating IGFBP-3 levels and/or genotype at the -202 locus are related to tissue expression of IGFBP-3 and/or to rates of proliferation and apoptosis.
Candidate drugs for cancer prevention, such as antiestrogens, antiandrogens, and retinoids, appear to act in large part by reducing cellular proliferation in at-risk tissues. There is evidence that the antiproliferative action of these compounds is mediated at least in part through up-regulation of IGFBP3 expression (20, 21, 23, 27). Indeed, a breast cancer prevention trial (43) has provided evidence that fenretinide (a synthetic derivative of retinoic acid) may reduce the risk of second breast cancers in premenopausal breast cancer survivors, in whom it increases plasma IGFBP-3 levels (27). The positive correlation we observed between circulating retinol levels and circulating IGFBP-3 levels is consistent with prior in vitro evidence that retinoids up-regulate IGFBP3 expression. Furthermore, the fact that the IGFBP-3-retinol relation is influenced by the -202 IGFBP3 polymorphism raises the possibility that the -202 IGFBP3 locus influences responsiveness to growth inhibitors whose action involves up-regulation of IGFBP3. This justifies studies to evaluate the possibility that the -202 IGFBP3 locus influences the efficacy of various agents proposed for cancer chemoprevention. There is a strong clinical need to define subpopulations for whom specific chemoprevention strategies are more or less likely to be effective, so as to optimize the value of such interventions from a risk/benefit point of view. IGFBP3 provides an example of a gene whose polymorphic variation may be relevant to the pharmacogenomics of cancer prevention.
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Footnotes |
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Received July 18, 2000.
Revised October 13, 2000.
Accepted November 21, 2000.
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J. M. Schildkraut, W. Demark-Wahnefried, R. M. Wenham, J. Grubber, A. S. Jeffreys, S. C. Grambow, J. R. Marks, P. G. Moorman, C. Hoyo, S. Ali, et al. IGF1 (CA)19 Repeat and IGFBP3 -202 A/C Genotypes and the Risk of Prostate Cancer in Black and White Men Cancer Epidemiol. Biomarkers Prev., February 1, 2005; 14(2): 403 - 408. [Abstract] [Full Text] [PDF]
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O. Fletcher, L. Gibson, N. Johnson, D. R. Altmann, J. M.P. Holly, A. Ashworth, J. Peto, and I. d. S. Silva Polymorphisms and Circulating Levels in the Insulin-Like Growth Factor System and Risk of Breast Cancer: A Systematic Review Cancer Epidemiol. Biomarkers Prev., January 1, 2005; 14(1): 2 - 19. [Abstract] [Full Text] [PDF]
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H.-L. Wong, K. DeLellis, N. Probst-Hensch, W.-P. Koh, D. Van Den Berg, H.-P. Lee, M. C. Yu, and S. A. Ingles A New Single Nucleotide Polymorphism in the Insulin-Like Growth Factor I Regulatory Region Associates with Colorectal Cancer Risk in Singapore Chinese Cancer Epidemiol. Biomarkers Prev., January 1, 2005; 14(1): 144 - 151. [Abstract] [Full Text] [PDF]
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M. Rohrbacher, A. Risch, S. Kropp, and J. Chang-Claude The A-336C Insulin-Like Growth Factor Binding Protein-3 Promoter Polymorphism Is Not a Modulator of Breast Cancer Risk in Caucasian Women Cancer Epidemiol. Biomarkers Prev., January 1, 2005; 14(1): 289 - 290. [Full Text] [PDF]
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K. DeLellis, S. Rinaldi, R. J. Kaaks, L. N. Kolonel, B. Henderson, and L. Le Marchand Dietary and Lifestyle Correlates of Plasma Insulin-Like Growth Factor-I (IGF-I) and IGF Binding Protein-3 (IGFBP-3): The Multiethnic Cohort Cancer Epidemiol. Biomarkers Prev., September 1, 2004; 13(9): 1444 - 1451. [Abstract] [Full Text] [PDF]
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Z. Ren, Q. Cai, X.-O. Shu, H. Cai, C. Li, H. Yu, Y.-T. Gao, and W. Zheng Genetic Polymorphisms in the IGFBP3 Gene: Association with Breast Cancer Risk and Blood IGFBP-3 Protein Levels among Chinese Women Cancer Epidemiol. Biomarkers Prev., August 1, 2004; 13(8): 1290 - 1295. [Abstract] [Full Text] [PDF]
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M. L. Slattery, W. Samowitz, K. Curtin, K. N. Ma, M. Hoffman, B. Caan, and S. Neuhausen Associations among IRS1, IRS2, IGF1, and IGFBP3 Genetic Polymorphisms and Colorectal Cancer Cancer Epidemiol. Biomarkers Prev., July 1, 2004; 13(7): 1206 - 1214. [Abstract] [Full Text] [PDF]
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J. H. Lai, D. Vesprini, W. Zhang, M. J. Yaffe, M. Pollak, and S. A. Narod A Polymorphic Locus in the Promoter Region of the IGFBP3 Gene Is Related to Mammographic Breast Density Cancer Epidemiol. Biomarkers Prev., April 1, 2004; 13(4): 573 - 582. [Abstract] [Full Text] [PDF]
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M. Rosilio, W. F. Blum, D. J. Edwards, E. P. Shavrikova, D. Valle, S. W. J. Lamberts, E. M. Erfurth, S. M. Webb, R. J. Ross, K. Chihara, et al. Long-Term Improvement of Quality of Life During Growth Hormone (GH) Replacement Therapy in Adults with GH Deficiency, as Measured by Questions on Life Satisfaction-Hypopituitarism (QLS-H) J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1684 - 1693. [Abstract] [Full Text] [PDF]
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L. Li, M. S. Cicek, G. Casey, and J. S. Witte No Association between Genetic Polymorphisms in IGF-I and IGFBP-3 and Prostate Cancer Cancer Epidemiol. Biomarkers Prev., March 1, 2004; 13(3): 497 - 498. [Full Text]
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 F. Modugno Ovarian Cancer and Polymorphisms in the Androgen and Progesterone Receptor Genes: A HuGE Review Am. J. Epidemiol., February 15, 2004; 159(4): 319 - 335. [Abstract] [Full Text] [PDF]
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J. Eng-Wong, S. D. Hursting, D. Venzon, S. N. Perkins, and J. A. Zujewski Effect of Raloxifene on Insulin-Like Growth Factor-I, Insulin-Like Growth Factor Binding Protein-3, and Leptin in Premenopausal Women at High Risk for Developing Breast Cancer Cancer Epidemiol. Biomarkers Prev., December 1, 2003; 12(12): 1468 - 1473. [Abstract] [Full Text] [PDF]
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 A. Decensi, U. Veronesi, R. Miceli, H. Johansson, L. Mariani, T. Camerini, M. G. Di Mauro, E. Cavadini, G. De Palo, A. Costa, et al. Relationships between Plasma Insulin-like Growth Factor-I and Insulin-like Growth Factor Binding Protein-3 and Second Breast Cancer Risk in a Prevention Trial of Fenretinide Clin. Cancer Res., October 15, 2003; 9(13): 4722 - 4729. [Abstract] [Full Text] [PDF]
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A. M. Y. Nomura, G. N. Stemmermann, J. Lee, and M. N. Pollak Serum Insulin-like Growth Factor I and Subsequent Risk of Colorectal Cancer among Japanese-American Men Am. J. Epidemiol., September 1, 2003; 158(5): 424 - 431. [Abstract] [Full Text] [PDF]
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 L. Wang, T. Habuchi, N. Tsuchiya, K. Mitsumori, C. Ohyama, K. Sato, H. Kinoshita, T. Kamoto, A. Nakamura, O. Ogawa, et al. Insulin-like Growth Factor-binding Protein-3 Gene -202 A/C Polymorphism Is Correlated with Advanced Disease Status in Prostate Cancer Cancer Res., August 1, 2003; 63(15): 4407 - 4411. [Abstract] [Full Text] [PDF]
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T. B. Twickler, M. J. M. Cramer, G. M. Dallinga-Thie, M. J. Chapman, D. W. Erkelens, and H. P. F. Koppeschaar Adult-Onset Growth Hormone Deficiency: Relation of Postprandial Dyslipidemia to Premature Atherosclerosis J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2479 - 2488. [Full Text] [PDF]
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M. E. DeVries, H. Cao, J. Wang, L. Xu, A. A. Kelvin, L. Ran, L. A. Chau, J. Madrenas, R. A. Hegele, and D. J. Kelvin Genomic Organization and Evolution of the CX3CR1/CCR8 Chemokine Receptor Locus J. Biol. Chem., March 28, 2003; 278(14): 11985 - 11994. [Abstract] [Full Text] [PDF]
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Y. S. Chang, L. Wang, D. Liu, L. Mao, W. K. Hong, F. R. Khuri, and H.-Y. Lee Correlation between Insulin-like Growth Factor-binding Protein-3 Promoter Methylation and Prognosis of Patients with Stage I Non-Small Cell Lung Cancer Clin. Cancer Res., December 1, 2002; 8(12): 3669 - 3675. [Abstract] [Full Text] [PDF]
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 M. S. Sandhu, D. B. Dunger, and E. L. Giovannucci Insulin, Insulin-Like Growth Factor-I (IGF-I), IGF Binding Proteins, Their Biologic Interactions, and Colorectal Cancer J Natl Cancer Inst, July 3, 2002; 94(13): 972 - 980. [Abstract] [Full Text] [PDF]
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 M. Niebert, C. Rogel-Gaillard, P. Chardon, and R. R. Tonjes Characterization of Chromosomally Assigned Replication-Competent Gamma Porcine Endogenous Retroviruses Derived from a Large White Pig and Expression in Human Cells J. Virol., February 22, 2002; 76(6): 2714 - 2720. [Abstract] [Full Text] [PDF]
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A. Decensi, H. Johansson, R. Miceli, L. Mariani, T. Camerini, E. Cavadini, M. G. Di Mauro, A. Barreca, A. G. Gonzaga, S. Diani, et al. Long-Term Effects of Fenretinide, a Retinoic Acid Derivative, on the Insulin-like Growth Factor System in Women with Early Breast Cancer Cancer Epidemiol. Biomarkers Prev., October 1, 2001; 10(10): 1047 - 1053. [Abstract] [Full Text] [PDF]
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