Insulin-like growth factor I (IGF-I) stimulates cell proliferation and can enhance the development of tumours in different organs. Epidemiological studies have shown that an elevated level of circulating IGF-I is associated with increased risk of breast cancer, as well as of other cancers. Most of circulating IGF-I is bound to an acid-labile subunit and to one of six insulin-like growth factor binding proteins (IGFBPs), among which the most important are IGFBP-3 and IGFBP-1. Polymorphisms of the IGF1 gene and of genes encoding for the major IGF-I carriers may predict circulating levels of IGF-I and have an impact on cancer risk. We tested this hypothesis with a case–control study of 807 breast cancer patients and 1588 matched control subjects, nested within the European Prospective Investigation into Cancer and Nutrition. We genotyped 23 common single nucleotide polymorphisms in IGF1, IGFBP1, IGFBP3 and IGFALS, and measured serum levels of IGF-I and IGFBP-3 in samples of cases and controls. We found a weak but significant association of polymorphisms at the 5′ end of the IGF1 gene with breast cancer risk, particularly among women younger than 55 years, and a strong association of polymorphisms located in the 5′ end of IGFBP3 with circulating levels of IGFBP-3, which confirms previous findings. Common genetic variation in these candidate genes does not play a major role in altering breast cancer risk in Caucasians.
IGF-I; IGFBP-3; IGFBP-1; IGFALS; single nucleotide polymorphisms; breast cancer
The acid-labile subunit (ALS) acts in the insulin-like growth (IGF) system by binding circulating IGF1 in a ternary complex with binding protein (IGFBP)-3 to prevent IGF1 from crossing the endothelial barrier. Given the role of the IGF system in prostate cancer, ALS may influence carcinogenesis by modulating IGF1 levels or bioavailability.
Materials and Methods
We undertook a prospective study nested in the Physicians’ Health Study to examine ALS, free IGF1 and prostate cancer. We assayed circulating levels of ALS and IGF components among 545 incident cases and 545 matched controls. We calculated relative risks and 95% confidence intervals (RR, 95% CI) adjusted for lifestyle factors, total IGF1 and IGFBP3.
ALS was positively correlated with total IGF1 (r=0.58), IGFBP3 (r=0.68), and free IGF1 (r=0.36). Comparing highest versus lowest quartiles, we found no association between free IGF1 and prostate cancer risk (0.9, 0.6–1.3). In contrast, ALS was positively associated with risk among men in the 2nd (1.5, 1.0–2.3), 3rd (1.6, 1.1–2.5) and 4th quartiles (1.4, 0.9–2.1) compared to lowest quartile. The association was stronger for advanced stage tumors (2.0, 0.8–4.6). Among men with low ALS, high total IGF1 was associated with a substantial increase in advanced prostate cancer (9.3, 1.7–51.3), while high IGF1 did not confer risk for those with higher ALS levels.
Plasma ALS is positively associated with prostate cancer risk, and may interact biologically with IGF1 to affect carcinogenesis. These data provide further support for the role of the IGF axis in prostate cancer.
IGF system; acid labile subunit; prostate cancer; epidemiology
Experimental evidence suggests that an overexpression of insulin-like growth factor-I (IGF-I) is implicated in human pancreatic tumors. Increased IGF-II and decreased insulin-like growth factor binding protein-3 (IGFBP-3) serum concentrations have been linked to a number of other cancers.
We conducted a nested case-control study in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort of men and women 55–74 years of age at baseline, to test whether pre-diagnostic circulating IGF-I, IGF-II, IGFBP-3, andIGF-I/IGFBP-3 molar ratio concentrations were associated with exocrine pancreatic cancer risk. Between 1994 and 2006, 187 incident cases of pancreatic adenocarcinoma occurred (follow-up to 11.7 years). Two controls (n=374), who were alive at the time the case was diagnosed, were selected for each case and matched by age, race, sex and date of blood draw. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression, adjusting for smoking.
IGF-I, IGF-II, and IGFBP-3 concentrations were not significantly associated with pancreatic cancer (highest compared with lowest quartile, OR=1.58, 95% CI 0.91–2.76, p-trend=0.25; OR=0.86, 95% CI 0.49–1.50, p-trend=0.31; and OR=0.88, 95% CI 0.51–1.51, p-trend=0.47, respectively). However, a significant positive trend was observed with high IGF-I/IGFBP-3 molar ratio levels (highest compared with lowest quartile OR=1.54, 95% CI 0.89–2.66, p-trend=0.04).
A higher IGF-I/IGFBP-3 molar ratio represents increased free IGF-I, which maybe a risk factor for pancreatic cancer.
Our results highlight the importance of this biomarker for further investigation in large prospective cohort studies and pooled analysis with other prospective cohorts.
IGF-I; IGF-II; IGFBP-3; IGF-I/IGFBP-3; Pancreatic
Insulin-like growth factor-I (IGF-I) and its major binding protein IGFBP-3 have been implicated in breast carcinogenesis. We examined the associations between genetic variants and circulating levels of IGF-I and IGFBP-3 with proliferative benign breast disease (BBD), a marker of increased breast cancer risk, in the Nurses’ Health Study II (NHSII). Participants were 359 pathology-confirmed proliferative BBD cases and 359 matched controls. Circulating IGF-I and IGFBP-3 levels were measured in blood samples collected between 1996 and 1999. Thirty single nucleotide polymorphisms (SNPs) in IGF-I, IGFBP-1, and IGFBP-3 genes were selected using a haplotype tagging approach and genotyped in cases and controls. Circulating IGF-I levels were not associated with proliferative BBD risk. Higher circulating IGFBP-3 levels were significantly associated with increased risk of proliferative BBD (highest vs. lowest quartile odds ratio (OR) (95% confidence interval (CI)), 1.70 (1.06–2.72); p-trend = 0.03). The minor alleles of two IGFBP-3 SNPs were associated with lower proliferative BBD risk (homozygous variant vs. homozygous wild-type OR (95% CI): rs3110697: 0.6 (0.4–0.9), p-trend = 0.02; rs2132570: 0.2 (0.1–0.6), p-trend = 0.02). Three other IGFBP-3 SNPs (rs2854744, rs2960436, and rs2854746) were significantly associated with circulating IGFBP-3 levels (p < 0.01). Although these SNPs were not significantly associated with proliferative BBD risk, there was suggestive evidence that the alleles associated with higher circulating IGFBP-3 levels were also associated with higher risk of proliferative BBD. These results suggest that genetic variants and circulating levels of IGFBP-3 may play a role in the early stage of breast carcinogenesis.
IGF-I; IGFBP-3; Circulating levels; Genetic Variation; Proliferative BBD
Insulin-like growth factors (IGF-I, IGF-II) and their binding proteins (IGFBP-1-6) play a key role in cell proliferation, differentiation and apoptosis, suggesting possible involvement in carcinogenesis. Several epidemiological studies show associations of IGFs with prostate cancer. We searched the published literature for all studies relating levels of IGFs or IGFBPs with prostate cancer. We performed random effects meta-analysis to calculate summary odds ratios. The number of studies (prostate cancer cases) included in each meta-analysis were 42 (7,481) IGF-I; 10 (923) IGF-II; 3 (485) IGFBP-1; 5 (577) IGFBP-2; 29 (6,541) IGFBP-3; and 11 (3,545) IGF-1:IGFBP-3 ratio. The pooled odds ratios (95% confidence intervals) per standard deviation increase in peptide, were: IGF-I, OR = 1.21 (1.07, 1.36); IGF-II, OR = 1.17 (0.93, 1.47); IGFBP-1, OR = 1.21 (0.62, 2.33); IGFBP-2, OR = 1.18 (0.90, 1.54); IGFBP-3, OR = 0.88 (0.79, 0.98); IGFI:IGFBP-3 ratio, OR = 1.10 (0.97, 1.24). For all exposures, there was substantial heterogeneity (all I2 > 75%), partly explained by study design: the magnitude of associations was smaller in prospective versus retrospective studies, and for IGFBP-3 the inverse association with prostate cancer risk was seen in retrospective but not prospective studies. There was weak evidence that associations of IGF-I and IGFBP-3 with prostate cancer were stronger for advanced disease. Our meta-analysis confirms that raised circulating lGF-I is positively associated with prostate cancer risk. Associations between IGFBP-3 and prostate cancer were inconsistent, and there was little evidence for a role of IGF-II, IGFBP-1 or IGFBP-2 in prostate cancer risk.
prostate cancer; meta-analysis; insulin-like growth factor; insulin-like growth factor binding protein
Insulin-like growth factor (IGF)-I induces growth in pancreatic cancer cells and blockade of the IGF-I receptor has antitumour activity. The association of plasma IGF-I and IGF binding protein-3 (IGFBP-3) with pancreatic cancer risk has been investigated in two small studies, with conflicting results. We conducted a nested case–control study within four large, prospective cohorts to investigate whether prediagnostic plasma levels of IGF-I, IGF-II, and IGFBP-3 were associated with pancreatic cancer risk. Plasma levels in 212 cases and 635 matched controls were compared by conditional logistic regression, with adjustment for other known pancreatic cancer risk factors. No association was observed between plasma levels of IGF-I, IGF-II, or IGFBP-3 and incident diagnosis of pancreatic cancer. Relative risks for the highest vs the lowest quartile of IGF-I, IGF-II, and IGFBP-3 were 0.94 (95% confidence interval (CI), 0.60–1.48), 0.96 (95% CI, 0.61–1.52), and 1.21 (95% CI, 0.75–1.92), respectively. The relative risk for the molar ratio of IGF-I and IGFBP-3, a surrogate measure for free IGF-I, was 0.84 (95% CI, 0.54–1.31). Additionally, no association was noted in stratified analyses or when requiring longer follow-up. In four prospective cohorts, we found no association between the risk of pancreatic cancer and prediagnostic plasma levels of IGF-I, IGF-II, or IGFBP-3.
pancreatic cancer; insulin-like growth factor; insulin-like growth factor binding protein; insulin
Some, but not all, published results have shown an association between circulating blood levels of some insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) and the subsequent risk for prostate cancer.
To assess the association between levels of IGFs and IGFBPs and the subsequent risk for prostate cancer.
Studies identified in PubMed, Web of Science, and CancerLit.
The principal investigators of all studies that published data on circulating concentrations of sex steroids, IGFs, or IGFBPs and prostate cancer risk using prospectively collected blood samples were invited to collaborate.
Investigators provided individual participant data on circulating concentrations of IGF-I, IGF-II, IGFBP-II, and IGFBP-III and participant characteristics to a central data set in Oxford, United Kingdom.
The study included data on 3700 men with prostate cancer and 5200 control participants. On average, case patients were 61.5 years of age at blood collection and received a diagnosis of prostate cancer 5 years after blood collection. The greater the serum IGF-I concentration, the greater the subsequent risk for prostate cancer (odds ratio [OR] in the highest vs. lowest quintile, 1.38 [95% CI, 1.19 to 1.60]; P < 0.001 for trend). Neither IGF-II nor IGFBP-II concentrations were associated with prostate cancer risk, but statistical power was limited. Insulin-like growth factor I and IGFBP-III were correlated (r = 0.58), and although IGFBP-III concentration seemed to be associated with prostate cancer risk, this was secondary to its association with IGF-I levels. Insulin-like growth factor I concentrations seemed to be more positively associated with low-grade than high-grade disease; otherwise, the association between IGFs and IGFBPs and prostate cancer risk had no statistically significant heterogeneity related to stage or grade of disease, time between blood collection and diagnosis, age and year of diagnosis, prostate-specific antigen level at recruitment, body mass index, smoking, or alcohol intake.
Insulin-like growth factor concentrations were measured in only 1 sample for each participant, and the laboratory methods to measure IGFs differed in each study. Not all patients had disease stage or grade information, and the diagnosis of prostate cancer may differ among the studies.
High circulating IGF-I concentrations are associated with a moderately increased risk for prostate cancer.
Insulin-like growth factor 1 (IGF1) and its main binding protein, IGF-binding protein 3 (IGFBP3), play an important role in cancer development. Circulating levels and functional polymorphisms of IGF1 and IGFBP3 may be biomarkers of cancer development. However, the results of published studies remain conflicting rather than conclusive. We searched MEDLINE and EMBASE databases for all published studies related to circulating levels and polymorphisms of IGF1 and IGFBP3 and cancer risk. In all, 96 studies and over 110 000 subjects were available for this meta-analysis. Higher IGF1 circulating levels significantly increased 15% of cancer risk (odds ratio (OR), 1.15, 95% confidence interval (CI), 1.03–1.29), especially among prostate, pre-menopausal breast and colorectal cancer patients, whereas higher concentrations of IGFBP3 significantly decreased the risk of advanced prostate cancer by 56% (OR, 0.44, 95% CI, 0.25–0.77). Meanwhile, IGFBP3 −202CC genotype was associated with an increased risk of prostate cancer with borderline significance (OR, 1.18, 95% CI, 0.99–1.41). Genotype–phenotype correlation analyses showed that circulating levels of IGFBP3 could be modified by its promoter polymorphism A−202C (P < 0.001). In conclusion, circulating levels of IGF1, IGFBP3 and IGFBP3 A−202C play a crucial role in carcinogenesis and could serve as susceptibility biomarkers for cancer development.
IGF1; IGFBP3; polymorphism; cancer risk; meta-analysis
Background: Insulin-like growth factor 1 (IGF-1) has antiapoptotic and mitogenic effects on various cell types, and raised IGF-1 levels are increasingly being implicated as potential risk factors for cancer.
Aims: To examine the relationship between IGF-1 and its major plasma binding protein, IGF binding protein 3 (IGFBP-3), and the risk of colorectal cancer.
Methods: We conducted a case-control study nested within the Northern Sweden Health and Disease Cohort. IGF-1 and IGFBP-3 were measured in prediagnostic plasma samples from 168 men and women who developed cancers of the colon (n=110) or rectum (n=58), and from 336 matched controls.
Results: Conditional logistic regression analyses showed an increase in colon cancer risk with increasing levels of IGF-1 (odds ratios (ORs) 1.00, 1.89, 2.30, 2.66; ptrend=0.03) and IGFBP-3 (ORs 1.00, 0.91, 1.80, 1.93; ptrend=0.02). Rectal cancer risk was inversely related to levels of IGF-1 (ORs 1.00, 0.45, 0.33, 0.33; ptrend=0.09) and IGFBP-3 (ORs 1.00, 0.75, 0.66, 0.49; ptrend=0.21). Mutual adjustments between IGF-1 and IGFBP-3 did not materially alter these relationships.
Conclusions: These results support earlier findings of increased risk of colon cancer in subjects with elevated plasma IGF-1. Our results however do not support the hypothesis that the risk of rectal cancer could also be directly related to IGF-1 levels.
insulin-like growth factor; colorectal cancer
The associations between serum concentrations of insulin-like growth factor-I (IGF-I), IGF-II and IGF-binding proteins (IGFBP)-3 and risk of breast cancer were investigated in a nested case–control study involving 117 cases (70 premenopausal and 47 postmenopausal at blood collection) and 350 matched controls within a cohort of women from the island of Guernsey, UK. Women using exogenous hormones at the time of blood collection were excluded. Premenopausal women in the top vs bottom third of serum IGF-I concentration had a nonsignificantly increased risk for breast cancer after adjustment for IGFBP-3 (odds ratio (OR) 1.71; 95% confidence interval (CI): 0.74–3.95; test for linear trend, P=0.21). Serum IGFBP-3 was associated with a reduction in risk in premenopausal women after adjustment for IGF-I (top third vs the bottom third: OR 0.49; 95% CI: 0.21–1.12, P for trend=0.07). Neither IGF-I nor IGFBP-3 was associated with risk in postmenopausal women and serum IGF-II concentration was not associated with risk in pre- or postmenopausal women. These data are compatible with the hypothesis that premenopausal women with a relatively high circulating concentration of IGF-I and low IGFBP-3 are at an increased risk of developing breast cancer.
breast cancer; insulin-like growth-factor-I (IGF-I); IGF-II; IGFBP-3; prospective study
Circulating insulin-like growth factor-one (IGF-I) and IGF binding protein-3 (IGFBP-3) levels have been associated with common diseases. Although family-based studies suggest that genetic variation contributes to circulating IGF-I and IGFBP-3 levels, analyses of associations with multiple IGF-I and IGFBP-3 single nucleotide polymorphisms (SNPs) have been limited, especially among African Americans. We evaluated 30 IGF-I and 15 IGFBP-3 SNPs and estimated diplotypes in association with plasma IGF-I and IGFBP-3 among 984 premenopausal African American and Caucasian women. In both races, IGFBP-3 rs2854746 (Ala32Gly) was positively associated with plasma IGFBP-3 (CC versus GG mean difference among Caucasians = 631 ng/ml, 95% confidence interval: 398, 864; African Americans = 897 ng/ml, 95% confidence interval: 656, 1138), and IGFBP-3 diplotypes with the rs2854746 GG genotype had lower mean IGFBP-3 levels than referent diplotypes with the CG genotype, while IGFBP-3 diplotypes with the CC genotype had higher mean IGFBP-3 levels. IGFBP-3 rs2854744 (−202 A/C) was in strong linkage disequilibrium with rs2854746 in Caucasians only, but was associated with plasma IGFBP-3 in both races. Eight additional IGFBP-3 SNPs were associated with 5% or greater differences in mean IGFBP-3 levels, with generally consistent associations between races. Twelve IGF-I SNPs were associated with 10% or greater differences in mean IGF-I levels, but associations were generally discordant between races. Diplotype associations with plasma IGF-I did not parallel IGF-I SNP associations. Our study supports that common IGFBP-3 SNPs, especially rs2854746, influence plasma IGFBP-3 levels among African Americans and Caucasians, but provides less evidence that IGF-I SNPs affect plasma IGF-I levels.
insulin-like growth factor I; insulin-like growth factor binding protein 3; genetic polymorphisms; women; African Americans
Circulating insulin-like growth factor-I (IGF-I) has been studied extensively in prostate cancer, but there is still little information about IGFs and IGF binding proteins (IGFBPs) in cancers detected by the prostate-specific antigen (PSA) test. Here we report the findings of a United Kingdom-based case-control study to investigate circulating IGFs and IGFBPs in PSA-detected prostate cancer with regard to their potential associations with different cancer stages or grades. PSA testing was offered to 110,000 men aged 50-69 years from 2002-2009. Participants with an elevated level of PSA (≥ 3.0 ng/ml) underwent prostate biopsy and measurements of blood serum IGF-I, IGF-II, IGFBP-2 and IGFBP-3 obtained at recruitment. We found that serum levels of IGF-II (OR per standard deviation increase: 1.16; 95%CI 1.08,1.24;ptrend<0.001), IGFBP-2 (1.18;1.06,1.31;ptrend<0.01) and IGFBP-3 (1.27;1.19,1.36;ptrend<0.001), but not IGF-I (0.99;0.93,1.04;ptrend=0.62), were associated with PSA-detected prostate cancer. After controlling for IGFBP-3, IGF-II was no longer associated (0.99;0.91,1.08;ptrend=0.62) and IGF-I was inversely associated (0.85;0.79,0.91;ptrend<0.001) with prostate cancer. In addition, no strong associations existed with cancer stage or grade. Overall, these findings suggest potentially important roles for circulating IGF-II, IGFBP-2 and IGFBP-3 in PSA-detected prostate cancer, in support of recent in vitro evidence. While our findings for IGF-I agree with previous results from PSA-screening trials, they contrast with positive associations in routinely-detected disease, suggesting that reducing levels of circulating IGF-I might not prevent the initiation of prostate cancer but might nonetheless prevent its progression.
case-control study; insulin-like growth factors; insulin-like growth factor binding proteins; prostate cancer
Increased concentrations of circulating insulin-like growth factor-I (IGF-I) or IGF-I relative to IGF-binding proteins (IGFBPs) are associated with increased risk of developing several forms of cancer. Conversely, exercise is linked with reduced risk. This study aims to investigate the effect of a low-intensity exercise program on circulating levels of IGF-I, IGFBP-1, and IGFBP-3, in previously sedentary males. Fourteen healthy men participated in cycle ergometer training at lactate threshold intensity for 60 min/day, 5 days/week for 6 weeks. After aerobic training, insulin sensitivity improved by 20%, while fasting insulin levels decreased by 13%. Simultaneously, low-intensity aerobic training decreased the circulating levels of IGF-I by 9%, while IGFBP-1 levels increased by 16%. An interesting finding was that higher pretraining level of IGF-I was associated with greater decline in IGF-I with training. Insulin-sensitizing low-intensity aerobic exercise is thus considered to be an effective method for downregulating IGF-I and upregulating IGFBP-1 levels.
Insulin-like growth factors (IGFs) are mediators of growth hormones; they have an influence on cell proliferation and differentiation. In addition, IGF-binding protein (IGFBP)-3 could suppress the mitogenic action of IGFs. Interestingly, tea polyphenols could substantially reduce IGF1 and increase IGFBP3. In this study, we evaluated the effects of smoking, green tea consumption, as well as IGF1, IGF2, and IGFBP3 polymorphisms, on lung cancer risk. Questionnaires were administered to obtain the subjects' characteristics, including smoking habits and green tea consumption from 170 primary lung cancer cases and 340 healthy controls. Genotypes for IGF1, IGF2, and IGFBP3 were identified by polymerase chain reaction. Lung cancer cases had a higher proportion of smoking, green tea consumption of less than one cup per day, exposure to cooking fumes, and family history of lung cancer than controls. After adjusting the confounding effect, an elevated risk was observed in smokers who never drank green tea, as compared to smokers who drank green tea more than one cup per day (odds ratio (OR) = 13.16, 95% confidence interval (CI) = 2.96–58.51). Interaction between smoking and green tea consumption on lung cancer risk was also observed. Among green tea drinkers who drank more than one cup per day, IGF1 (CA)19/(CA)19 and (CA)19/X genotypes carriers had a significantly reduced risk of lung cancer (OR = 0.06, 95% CI = 0.01–0.44) compared with IGF1 X/X carriers. Smoking-induced pulmonary carcinogenesis could be modulated by green tea consumption and their growth factor environment.
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) are 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.
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.
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.
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.
endometrial cancer; polymorphisms; genetics; IGF
Circulating levels of insulin-like growth factor I (IGF-1) and its main binding protein, IGF binding protein 3 (IGFBP-3), have been associated with risk of several types of cancer. Heritable factors explain up to 60% of the variation in IGF-1 and IGFBP-3 in studies of adult twins.
We systematically examined common genetic variation in 18 genes in the IGF signaling pathway for associations with circulating levels of IGF-1 and IGFBP-3. A total of 302 single nucleotide polymorphisms (SNPs) were genotyped in over 5500 Caucasian men and 5500 Caucasian women from the Breast and Prostate Cancer Cohort Consortium (BPC3).
After adjusting for multiple testing, SNPs in the IGF1 and SSTR5 genes were significantly associated with circulating IGF-1 (p<2.1×10−4); SNPs in the IGFBP3 and IGFALS genes were significantly associated with circulating IGFBP-3. Multi-SNP models explained R2=0.62% of the variation in circulating IGF-1 and 3.9% of the variation in circulating IGFBP-3. We saw no significant association between these multi-SNP predictors of circulating IGF-1 or IGFBP-3 and risk of prostate or breast cancers.
Common genetic variation in the IGF1 and SSTR5 genes appears to influence circulating IGF-1 levels, and variation in IGFBP3 and IGFALS appears to influence circulating IGFBP-3. However, these variants explain only a small percentage of the variation in circulating IGF-1 and IGFBP-3 in Caucasian men and women.
Further studies are needed to explore contributions from other genetic factors such as rare variants in these genes and variation outside of these genes.
insulin-like growth factors; genetic association; breast cancer; prostate cancer
Insulin-like growth factor 1 (IGF1) stimulates mitosis and inhibits apoptosis. Some published results have shown an association between circulating IGF1 and breast-cancer risk, but it has been unclear whether this relationship is consistent or whether it is modified by IGF binding protein 3 (IGFBP3), menopausal status, oestrogen receptor status or other factors. The relationship of IGF1 (and IGFBP3) with breast-cancer risk factors is also unclear. The Endogenous Hormones and Breast Cancer Collaborative Group was established to analyse pooled individual data from prospective studies to increase the precision of the estimated associations of endogenous hormones with breast-cancer risk.
Individual data on prediagnostic IGF1 and IGFBP3 concentrations were obtained from 17 prospective studies in 12 countries. The associations of IGF1 with risk factors for breast cancer in controls were examined by calculating geometric mean concentrations in categories of these factors. The odds ratios (ORs) with 95% CIs of breast cancer associated with increasing IGF1 concentrations were estimated by conditional logistic regression in 4790 cases and 9428 matched controls, with stratification by study, age at baseline, and date of baseline. All statistical tests were two-sided, and a p value of less than 0·05 was considered significant.
IGF1 concentrations, adjusted for age, were positively associated with height and age at first pregnancy, inversely associated with age at menarche and years since menopause, and were higher in moderately overweight women and moderate alcohol consumers than in other women. The OR for breast cancer for women in the highest versus the lowest fifth of IGF1 concentration was 1·28 (95% CI 1·14–1·44; p<0·0001). This association was not altered by adjusting for IGFBP3, and did not vary significantly by menopausal status at blood collection. The ORs for a difference in IGF1 concentration between the highest and lowest fifth were 1·38 (95% CI 1·14–1·68) for oestrogen-receptor-positive tumours and 0·80 (0·57–1·13) for oestrogen-receptor-negative tumours (p for heterogeneity=0·007).
Circulating IGF1 is positively associated with breast-cancer risk. The association is not substantially modified by IGFBP3, and does not differ markedly by menopausal status, but seems to be confined to oestrogen-receptor-positive tumours.
Cancer Research UK.
Insulin-like growth factor-1 (IGF1) and its most abundant binding protein, insulin-like growth factor binding protein-3 (IGFBP3), have been implicated in fibrotic lung diseases and persistent acute respiratory distress syndrome (ARDS) because of profibrogenic and antiapoptotic activity. Whether levels of circulating IGF1 and IGFBP3 are altered in ARDS, and whether they predict progression of and survival from ARDS remains unknown. This study aims to characterize circulating levels of IGF1 and IGFBP3 in patients at risk for ARDS in relation to (1) development of ARDS, and (2) mortality among ARDS cases.
In this case-cohort study, consecutive patients with risk factors for ARDS admitted to the intensive care unit (ICU) were enrolled and followed prospectively for development of ARDS. Cases were followed for all-cause mortality through Day 60. Of 2397 patients enrolled in the parent study, plasma samples were available in 531 (22%) patients (356 controls, 175 cases) from early in presentation. Total plasma IGF1 and IGFBP3 were measured.
After adjusting for relevant clinical covariates including severity of illness, IGF1 and IGFBP3 levels were significantly lower in ARDS cases than controls (odds ratio [OR], 0.58; P =0.006; OR, 0.57; P=0.0015, respectively). Among ARDS cases, IGF1 and IGFBP3 levels were significantly lower in the 78 (45%) non-survivors (hazard ratio [HR], 0.70; P =0.024; HR, 0.69; P=0.021, respectively).
Lower levels of circulating IGF1 and IGFBP3 were independently associated with ARDS case status. Furthermore, lower levels were associated with mortality among ARDS cases. This data supports a role of the IGF pathway in ARDS.
Adult Respiratory Distress Syndrome; Insulin-Like Growth Factor-1; Insulin-Like Growth Factor Binding Protein-3; Molecular Epidemiology; Serum Biomarkers
Insulin-like growth factors are implicated in the development of diabetic nephropathy. IGF-binding protein 2 (IGFBP2) and IGF2 are expressed in the kidney, but their associations with diabetic nephropathy are unclear. We therefore tested the hypothesis that circulating levels of IGF2 and IGFBP2 predict longitudinal renal function in individuals with type 2 diabetes.
Design and methods
IGFBP2 and IGF2 measurements were performed in 436 individuals (263 males) with type 2 diabetes. Linear mixed-effect regression analysis was used to model the relationship between plasma IGFBP2 concentration and longitudinal changes in estimated glomerular filtration rate (eGFR) over an 8-year period. Analyses were also performed for IGF1, IGF2, IGFBP1 and IGFBP3 concentrations as predictors of longitudinal renal outcomes.
High IGFBP2 concentration at baseline was associated with a decreased eGFR over an 8-year period (β=−0.02, (95% confidence interval −0.03 to −0.01), P<0.001). High IGFBP1, IGFBP2 and IGFBP3 were also associated with low baseline eGFR concentration.
This study demonstrates that IGFBP2 is a predictor of longitudinal deterioration of renal function in type 2 diabetes.
IGFBP2; longitudinal trends; renal function; real-world data
The liver is the primary source of circulating insulin-like growth factor (IGF)-I, yet the relation between IGFs and liver cancer is uncertain.
In a case–cohort study within a cohort of 29 133 male smokers we examined associations of serum IGF-I and IGF binding protein (IGFBP)-3 with liver cancer (50 cases).
Nonlinear associations between liver cancer and IGF-I and IGFBP-3 were observed (P=0.04 and P<0.01, respectively), strongest association at lowest levels (odds ratio (OR)=0.2, 95% confidence interval (CI)=0.1–0.7 for 80 vs 30 ng ml−1 of IGF-I; OR=0.2, 95% CI=0.1–0.6 for 1400 vs 700 ng ml−1 of IGFBP-3).
Low IGF-I and IGFBP-3 levels in male smokers are associated with increased risk of liver cancer.
insulin-like growth factor; IGF-I; incidence; men
The insulin-like growth factor (IGF) pathway is believed to play a pivotal role in thyroid carcinogenesis. Polymorphisms of IGF-1 and IGF binding protein-3 (IGFBP-3) have been associated with modulation of risk for the emergence of assorted common malignancies, but studies of the influence of such polymorphisms on risk of differentiated thyroid carcinoma (DTC) are lacking.
In a case-control study of 173 DTC patients, 101 patients with benign thyroid disease, and 401 controls, an unconditional logistical regression model adjusted for age and sex was applied to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between polymorphisms of IGF-1 and IGFBP-3 and DTC risk.
IGFBP-3 rs2132572 GA/AA genotypes were associated with a decreased risk of DTC (adjusted OR=0.6, 95% CI: 0.4–0.9), particularly multifocal DTC (adjusted OR=0.3, 95% CI: 0.1–0.7). The association with DTC was more evident in subjects with a first-degree family history of cancer (adjusted OR=0.4, 95% CI: 0.2–0.7, Pinteraction=0.013) and nondrinkers (adjusted OR=0.4, 95% CI: 0.2–0.7, Pinteraction=0.028). A 4 SNP haplotype of IGFBP-3 was associated with a decreased risk of DTC (adjusted OR=0.7, 95% CI: 0.5–1.0, P=0.030).
Our study suggests that polymorphic IGFBP-3 may be involved in susceptibility to DTC.
IGF-1; multifocal; genetic susceptibility; papillary thyroid carcinoma; case-control study
Recent studies have suggested that insulin-like growth factors (IGFs) and insulin-like growth factor binding proteins (IGFBPs) may be implicated in the development and progression of breast cancer. Prostate-specific antigen (PSA), a serine protease, may play a role in the regulation of IGFs' function through cleavage of IGFBP-3, resulting in release of active IGFs from IGFBP-3. As IGFs, IGFBPs and PSA are all present in breast cancer, possible associations among these proteins were speculated. In this study, we have measured PSA, IGF-I, IGF-II, IGFBP-1 and IGFBP-3 in tumour tissue cytosols from 200 women with primary breast cancer, and have examined relationships between IGFs or IGFBPs and PSA along with other markers, including p53 protein, steroid hormone receptors (oestrogen and progesterone), cathepsin-D, epidermal growth factor receptor, Her-2/neu protein, S-phase fraction and DNA ploidy. Correlations or associations between PSA and IGF-I, IGF-II, IGFBP-1 or IGFBP-3 were not observed. IGF-II was positively correlated with both IGFBP-3 and IGFBP-1. IGF-I was not associated with either of the two binding proteins, nor with IGF-II. Both IGF-II and IGFBP-3 were inversely associated with the oestrogen receptor, and IGFBP-3 was also positively associated with S-phase fraction. Our finding of IGF-II and IGFBP-3 in association with unfavourable prognostic indicators of breast cancer suggests that IGFs may be involved in the progression of breast cancer.
The insulin-like growth factor (IGF) axis plays a role in growth and progression of prostate cancer. High circulating IGF-1 levels have been associated with an increased risk of prostate cancer. Results for IGF binding protein 3 (IGFBP-3) are inconclusive. Some studies have indicated that the positive association with IGF-1 is observed only for low-grade prostate cancer (Gleason sum <7). We previously reported in the Health Professionals Follow-up Study (HPFS) a direct positive association between ELISA-measured plasma IGF-1 and IGFBP-3 and risk of prostate cancer (462 cases diagnosed after providing a blood specimen (between 1993 and 1995), but before February 1998). With additional follow-up through January 31st 2004, and 1331 case-control pairs in total, we were now able to investigate low-grade (Gleason sum <7, n=635) and high-grade (Gleason sum ≥7, n=515) prostate cancer separately. Matched odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. ORs of total prostate cancer comparing top to bottom quartiles were 1.41 (95% CI 1.12–1.78, p-trend=0.001) for IGF-1 and 1.58 (95% CI 1.24–2.01, p-trend=0.003) for IGFBP-3. IGF-1 was more strongly associated with low-grade (OR=1.61 top versus bottom quartile, 95% CI 1.16–2.25, p-trend=0.01), than with high-grade (OR=1.29, 95% CI 0.89–1.88, p-trend-0.12) prostate cancer (p-heterogeneity=0.08). We hypothesize that these findings reflect that high-grade prostate cancers are more autonomous, and, thus, less sensitive to the action of IGF-1 than low-grade cancers.
The insulin-like growth factors (IGFs) play a central role in controlling somatic growth in mammals and exert anabolic effects on most tissues, including bone. IGF action is mediated by the IGF-I receptor and additionally is regulated by six high-affinity IGF binding proteins (IGFBP-1 through IGFBP-6), of which IGFBP-4 and IGFBP-5 are most abundant in bone. The focus of this brief review is on the role of IGFBP-5 in bone biology. IGFBP-5 has been implicated as a pro-osteogenic factor in several studies but conversely has been shown to act as an inhibitor of bone formation, primarily by interfering with IGF actions on osteoblasts. These potentially contradictory effects of IGFBP-5 in bone are further complicated by observations indicating that IGFBP-5 additionally may function in an IGF-independent way, and may have been accentuated by differences in both experimental design and methodology among published studies. Suggestions are made for a more systematic approach to help discern the true roles of IGFBP-5 in bone physiology.
Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 10−8 (P = 3.3 × 10−101). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10−26). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10−21) and higher IGF-I (P = 4.9 × 10−9) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10−11, IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10−10, SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10−7), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.