Genetic polymorphisms involved in insulin-like growth factor (IGF) pathway in relation to mammographic breast density and IGF levels.

The insulin-like growth factor (IGF) pathway is believed to play a role in carcinogenesis of the mammary gland. Single nucleotide polymorphisms (SNPs) of IGF-I, IGF-binding protein-3 (IGFBP-3), IGF receptor 1, insulin receptor substrate 1, and phosphoinositide-3-kinase, catalytic, beta polypeptide genes, which are members of the IGF pathway, have been associated with risk of common cancers, breast density, and/or IGF levels but results remain inconclusive. Thus, we evaluated the association of 11 targeted IGF pathway SNPs with circulating IGF levels and mammographic breast density. Among 741 white premenopausal women, blood samples were collected at time of screening mammography, and plasma IGF-I and IGFBP-3 levels were measured by ELISA. Percent and absolute breast density were estimated using a computer-assisted method. Multivariate linear models were used to examine the associations. Women carrying increasing number of copies of the rare allele of IGF-I rs1520220 and rs6220 SNPs had increased percent breast density (P(trend) = 0.04 and 0.06, respectively). Carriers of increasing number of copies of the rare allele of phosphoinositide-3-kinase, catalytic, beta polypeptide rs361072 SNP had decreased percent (P(trend) = 0.04) and absolute (P(trend) = 0.02) breast density. An association of insulin receptor substrate 1 rs1801278 SNP with absolute density (P(trend) = 0.03) was also observed. All four IGFBP-3 SNPs (including rs2854744) were associated with IGF-I and IGFBP-3 levels. This study shows that several components of the IGF pathway are associated with breast density or IGF levels. Our findings provide additional support for the idea that several components of the IGF pathway may affect breast cancer risk and that this effect on breast cancer development may be mediated, at least in part, through its influence on the morphogenesis of breast tissue.     

Insulin-like growth factor-I, IGF-binding protein-3, and mammographic breast density.

Some studies have suggested that insulin-like growth factor (IGF) pathway is related to premenopausal breast density, one of the strongest known breast cancer risk factors. This study was designed specifically to test the hypothesis that higher levels of IGF-I and lower levels of IGF-binding protein (IGFBP)-3 are associated with high mammographic breast density among premenopausal but not among postmenopausal women. A total of 783 premenopausal and 791 postmenopausal healthy women were recruited during screening mammography examinations. Blood samples were collected at the time of mammography, and plasma IGF-I and IGFBP-3 levels were measured by ELISA. Mammographic breast density was estimated using a computer-assisted method. Spearman's partial correlation coefficients (r(s)) were used to evaluate the associations. Adjusted mean breast density was assessed by joint levels of IGF-I and IGFBP-3 using generalized linear models. Among premenopausal women, high levels of IGF-I and low levels of IGFBP-3 were independently correlated with high breast density (r(s) = 0.083; P = 0.021 and r(s) = -0.124; P = 0.0005, respectively). Correlation of IGF-I with breast density was stronger among women in the lowest tertile of IGFBP-3 than among those in the highest tertile of IGFBP-3 (r(s) = 0.138; P = 0.027 and r(s) = -0.039; P = 0.530, respectively). In contrast, the correlation of IGFBP-3 with breast density was stronger among women in the highest tertile of IGF-I than among those in the lowest tertile of IGF-I (r(s) = -0.150; P = 0.016 and r(s) = -0.008; P = 0.904, respectively). Women in the combined top tertile of IGF-I and bottom tertile of IGFBP-3 had higher mean breast density than those in the combined bottom tertile of IGF-I and top tertile of IGFBP-3 (53.8% versus 40.9%; P = 0.014). No significant association was observed among postmenopausal women. Our findings confirm that IGF-I and IGFBP-3 are associated with breast density among premenopausal women. They provide additional support for the idea that, among premenopausal women, these growth factors may affect breast cancer risk, at least in part, through their influence on breast tissue morphology as reflected on mammogram.     

A nested case-control study of stomach cancer and serum insulin-like growth factor (IGF)-1, IGF-2 and IGF-binding protein (IGFBP)-3

We conducted this study to investigate the association between serum levels of insulin-like growth factor (IGF)-1, IGF-2, and IGF-binding protein (IGFBP)-3 and the incidence of stomach cancer. A nested case-control study of 161 stomach cancer incidences and 314 matched controls was established within the Japan Collaborative Cohort Study. The adjusted ORs for IGF-1 quartile ranged from 0.84 and 1.13, but these were not statistically significant. Further, higher IGF-2 levels did not significantly correlate with the incidence of stomach cancer. A tendency for the risk of stomach cancer to decrease with increasing IGFBP-3 level was observed, but without statistical significance. A slight decrease in risk was seen with an increase in IGFBP-3 level, but neither change was statistically significant. To conclude, we found no association between IGF-1, IGF-2, or IGFBP-3 serum levels and the risk of stomach cancer. As this association has not been established, these findings need to be confirmed in future studies.     

Serum C-peptide, insulin-like growth factor (IGF)-I, IGF-binding proteins, and colorectal cancer risk in women

BACKGROUND: Leading a Western lifestyle, being overweight, and being sedentary are associated with an increased risk of colorectal cancer. Recent theories propose that the effects of these risk factors may be mediated by increases in circulating insulin levels and in the bioactivity of insulin-like growth factor (IGF)-I. To test this hypothesis, we conducted a case-control study nested within a cohort of 14 275 women in New York. METHODS: We used blood samples that had been obtained from these women from March 1985 through June 1991 and stored in a biorepository. C-peptide (a marker for insulin secretion), IGF-I, and IGF-binding proteins (IGFBPs)-1, -2, and -3 were assayed in the serum of 102 women who subsequently developed colorectal cancer and 200 matched control subjects. Logistic regression was used to relate cancer risk to these peptide levels, by adjustment for other risk factors. All statistical tests used are two-sided. RESULTS: Colorectal cancer risk increased with increasing levels of C-peptide (P:(trend) =.001), up to an odds ratio (OR) of 2. 92 (95% confidence interval [CI] = 1.26-6.75) for the highest versus the lowest quintiles, after adjustment for smoking. For colon cancer alone (75 case subjects and 146 control subjects), ORs increased up to 3.96 (95% CI = 1.49-10.50; P:(trend) <.001) for the highest versus the lowest quintiles. A statistically significant decrease in colorectal cancer risk was observed for increasing levels of IGFBP-1 (P:(trend) =.02; OR in the upper quintile = 0.48 [95% CI = 0.23-1. 00]), as well as for the highest quintile of IGFBP-2 levels (P:(trend) =.06; OR = 0.38 [95% CI = 0.15-0.94]). Colorectal cancer risk showed a modest but statistically nonsignificant positive association with levels of IGF-I and was statistically significantly increased for the highest quintile of IGFBP-3 (OR = 2.46 [95% CI = 1. 09-5.57]). CONCLUSIONS: Chronically high levels of circulating insulin and IGFs associated with a Western lifestyle may increase colorectal cancer risk, possibly by decreasing IGFBP-1 and increasing the bioactivity of IGF-I.     

Insulin-like growth factor (IGF)-I, IGF-binding protein-3 and colorectal adenomas in Japanese men.

Several epidemiological studies have found that high levels of plasma insulin-like growth factor (IGF)-I and low levels of IGF-binding protein (IGFBP)-3 are related to an increased risk of colorectal cancer or late-stage adenomas. We examined the relation of body mass index, fasting and 2-h postload plasma glucose levels and plasma concentrations of IGF-I and IGFBP-3 to colorectal adenomas in middle-aged Japanese men. The study subjects comprised 157 cases of histologically diagnosed colorectal adenomas and 311 controls with normal colonoscopy or non-polyp benign lesions in a consecutive series of 803 men receiving a preretirement health examination at two hospitals of the Self Defense Forces (SDF). After adjustment for rank in the SDF, hospital, smoking and IGFBP-3, a statistically nonsignificant modest increase in the prevalence odds of colorectal adenomas was observed for the highest versus the lowest quartile level of IGF-I. The increase was slightly greater with further adjustment for 2-h glucose concentrations (adjusted odds ratio 1.8, 95% confidence interval 1.0-4.5, trend P=0.06). Men with high levels of IGFBP-3 showed only a minimal decrease in risk after adjustment for IGF-I. The association with IGF-I was less evident for advanced adenomas (>5 mm in size or tubulovillous/villous). Fasting and 2-h glucose and body mass index were more strongly positively associated with colorectal adenomas than IGF-I, especially with advanced adenomas, independently of IGF-I and IGFBP-3. The findings suggest that plasma IGF-I and IGFBP-3 may be involved in colorectal tumorigenesis regardless of the stage in growth of adenoma, but not as a mediator for the effects of being overweight or of hyperglycemia.     

Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3

BACKGROUND: Insulin-like growth factor-I (IGF-I) is a potent mitogen for normal and neoplastic cells, whereas IGF-binding protein-3 (IGFBP-3) inhibits cell growth in many experimental systems. Acromegalics, who have abnormally high levels of growth hormone and IGF-I, have higher rates of colorectal cancer. We therefore examined associations of plasma levels of IGF-I and IGFBP-3 with the risk of colorectal cancer in a prospective case-control study nested in the Physicians' Health Study. METHODS: Plasma samples were collected at baseline from 14916 men without diagnosed cancer. IGF-I, IGF-II, and IGFBP-3 were assayed among 193 men later diagnosed with colorectal cancer during 14 years of follow-up and among 318 age- and smoking-matched control subjects. All P values are two-sided. RESULTS: IGFBP-3 levels correlated with IGF-I levels (r=.64) and with IGF-II levels (r=.90). After controlling for IGFBP-3, age, smoking, body mass index (weight in kg/[height in m]2), and alcohol intake, men in the highest quintile for IGF-I had an increased risk of colorectal cancer compared with men in the lowest quintile (relative risk [RR]=2.51; 95% confidence interval [CI]=1.15-5.46; P for trend = .02). After controlling for IGF-I and other covariates, men with higher IGFBP-3 had a lower risk (RR=0.28; 95% CI=0.12-0.66; P for trend = .005, comparing extreme quintiles). The associations were consistent during the first and the second 7-year follow-up intervals and among younger and older men. IGF-II was not associated with risk. CONCLUSIONS: Our findings suggest that circulating IGF-I and IGFBP-3 are related to future risk of colorectal cancer.     

Insulin-like growth factor (IGF)-1, IGF-binding protein-3, and pancreatic cancer in male smokers.

To investigate whether insulin-like growth factor (IGF)-1 and IGF-binding protein-3 (IGFBP-3) are prospectively associated with exocrine pancreatic cancer, we conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of 29,133 male Finnish smokers, aged 50-69 years. To avoid the potential influence of subclinical cancer on IGF-1 and IGFBP-3, all subjects in this study were alive without clinical evidence of cancer during their 5th year of the cohort follow-up. Four hundred randomly selected cohort controls and 93 incident pancreatic adenocarcinoma cases that occurred between their 5th follow-up year through 1997 (i.e., up to 12.7 years of follow-up) were included in this study. Concentrations of IGF-1 and IGFBP-3 were measured in serum samples obtained at baseline using ELISA. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression models, adjusted for confounders. Neither IGF-1, IGFBP-3, nor the IGF-1:IGFBP-3 molar ratio was significantly associated with pancreatic cancer: highest compared to lowest tertile, OR = 0.67, 95% CI 0.37-1.21, P trend = 0.17; OR = 0.70, 95% CI 0.38-1.27, P trend = 0.12; and OR = 0.85, 95% CI 0.50-1.46, P trend = 0.54, respectively. Our results do not support the hypothesis that serum IGF-1 and IGFBP-3 concentrations are associated with pancreatic cancer risk among male smokers. Further studies are necessary to evaluate these associations in other populations.     

Lifestyle correlates of plasma insulin-like growth factor I and insulin-like growth factor binding protein 3 concentrations.

Plasma levels of insulin-like growth factor I (IGF-I) have been associated with risk of a number of cancers and other diseases. We examined the cross-sectional association of plasma IGF-I and IGF-binding protein 3 (IGFBP-3) levels with age, smoking, physical activity, and reproductive and menopausal factors in 1037 healthy women. Adjusted least-square mean hormone levels across categories of lifestyle factors were calculated by linear regression. Age was inversely associated with IGF-I levels. In multivariate analyses, a higher body mass index (BMI) was associated with higher IGFBP-3 levels (BMI <21 versus >/=29 kg/m(2), 3879 versus 4080 ng/ml; P for trend = 0.01). Current use of hormone replacement therapy (HRT) was associated with a lower IGF-I, with oral estrogen being associated with the lowest levels (non-use of HRT versus oral estrogen + progesterone versus oral estrogen: 181 versus 143 versus 116 ng/ml; P for all comparisons /=4: 212 versus 180 ng/ml; P for trend = 0.003). We conclude that age and HRT use, particularly oral estrogen alone, were inversely associated with IGF-I levels. BMI was positively associated with IGFBP-3 levels. This is the first report of an inverse association of circulating IGF-I levels with parity. This association may represent one mechanism by which parity exerts its protective effect on some cancers.     

Nonlinear relationship of insulin-like growth factor (IGF)-I and IGF-I/IGF-binding protein-3 ratio with indices of adiposity and plasma insulin concentrations (Sweden)

Objective: In this study we test the hypothesis of a nonlinear relationship of IGF-I with indices of body fat such as body mass index (BMI), insulin, and leptin. Methods: The controls used in three case–control cancer studies nested in the Northern Sweden Health and Disease Cohort, were combined for this analysis. Measurements of plasma IGF-I, IGFBP-3, insulin, and leptin were available for 445 men and 391 women. Results: In both men and women we found the highest mean IGF-I levels in subjects with BMI between 24 and 26. IGF-I concentrations decreased toward BMI 20 and BMI > 30 in men; however, the results for women did not reach statistical significance. The molar ratio of IGF-I/IGFBP-3 showed a similar profile to that of IGF-I, although much less pronounced. The observed peak mean IGF-I levels in the second quintiles of insulin and leptin in men supported these findings. No significant variation of mean IGF-I levels across quintiles of insulin and leptin were observed in women. Conclusions: The results of this study provide evidence that IGF-I plasma concentrations vary substantially over a wide range of body weight and that the relationship is nonlinear.     

Dietary correlates of plasma insulin-like growth factor I and insulin-like growth factor binding protein 3 concentrations.

Plasma levels of insulin-like growth factor I (IGF-I) have been associated with risk of several cancers. Although protein-calorie malnutrition is known to decrease IGF-I levels, few published studies have related diet to IGF-I levels in well-nourished humans. We examined the cross-sectional association of plasma IGF-I and IGF-binding protein 3 (IGFBP-3) levels with intakes of alcohol, energy, macronutrients, micronutrients, and specific foods in 1037 healthy women. Adjusted mean hormone levels across categories of dietary variables were calculated by linear regression. Results were adjusted for non-dietary factors found to be associated with IGF levels. Total energy intake was positively associated with IGF-I levels when adjusted for covariates. Adjusted mean levels of IGF-I (ng/ml) across increasing quintiles of energy intake were 181, 185, 191, 199, and 195 (P for the linear trend = 0.006). In other multivariate analyses, energy-adjusted fat and carbohydrate intake had no association with IGF-I levels. The most consistent finding was a positive association between protein intake with circulating IGF-I concentration (174, 188, 201, 192, and 196 ng/ml across quintiles of protein intake; P = 0.002), which was largely attributable to milk intake. Adjusted mean levels of IGF-I (ng/ml) across increasing quartiles of milk intake were 183, 189, 188, and 200 (P = 0.01). Higher fat intake, in particular saturated fat, was associated with lower levels of IGFBP-3. We conclude that higher energy, protein, and milk intakes were associated with higher levels of IGF-I. These associations raise the possibility that diet could affect cancer risk through influencing IGF-I level.     

Effects of a 9-month strength training intervention on insulin, insulin-like growth factor (IGF)-I, IGF-binding protein (IGFBP)-1, and IGFBP-3 in 30-50-year-old women.

We assessed the effects of twice weekly strength training on several proposed risk factors for breast and colon cancer: body fat, waist circumference, fasting insulin, fasting glucose, insulin-like growth factor I (IGF-I), and several IGF-binding proteins. Fifty-four healthy women, 30-50 years old, were randomized to no-contact control or treatment: 15 weeks of supervised strength training followed by 6 months of unsupervised training. Fifteen-week changes included reductions in percentage of body fat, fasting insulin, fasting glucose, and IGF-I that were larger in the treatment than control participants (treatment versus control mean +/- SE: % body fat -1.97 +/- 0.42 versus -0.43 +/- 0.40, P = 0.01; insulin (uU/ml) -0.29 +/- 0.35 versus 0.81 +/- 0.38, P = 0.055; glucose (mg/dl) -1.92 +/- 1.27 versus 1.21 +/- 1.36, P = 0.13; and IGF-I (ng/ml) -30.47 +/- 9.75 versus 5.86 +/- 10.44, P = 0.02). There was no treatment effect on IGF-binding proteins 1 and 3 or either of two surrogate measures of free IGF-I. By 39 weeks changes in percentages of body fat were largely maintained; IGF-I returned to baseline levels in the treatment group but remained 15% lower in treatment compared with control participants. Strength training produced favorable changes in several proposed cancer risk factors. The importance of these changes to long-term cancer prognosis, diagnosis, and/or recurrence remains to be determined.     

Insulin-like growth factor (IGF)-I and IGF-binding protein 3 and the risk of premenopausal breast cancer: a meta-analysis of literature

Biologic evidence suggests substantial effect of insulin-like growth factor (IGF)-I in mammary cell carcinogenesis. However, controversy remains regarding the association between circulating IGF-I levels and the risk of premenopausal breast cancer in epidemiologic studies. In addition, the association of IGF-binding protein (IGFBP)-3, which binds with and modifies the effect of IGF-I, is unclear. To clarify these associations, we performed a meta-analysis of all the published studies. A systematic review of literature was conducted. Eligible study designs were nested case-control and population-based case-control studies that give estimates for menopausal women. The studies published between January 1990 and March 2003 were obtained from Medline. We obtained 7 studies, consisting of 688 premenopausal incident breast cancer cases and 1,366 controls, for our final evaluation. Summary statistics were odds ratios (ORs) comparing the highest and the lowest levels of IGF-I and IGFBP-3 adjusted for confounders other than IGF-I or IGFBP-3. There was neither evidence of heterogeneity between studies nor evidence of publication bias. The confounders considered and the contrast used for the ORs were the major source of variation. The subjects with higher circulating levels of IGF-I had marginally significant increased risk of breast cancer with an OR of 1.74 (95% CI = 0.97-3.13; p = 0.06). No significant difference was observed for IGFBP-3 group (OR = 1.60; 95% CI = 0.84-3.02; p = 0.15). In conclusion, we found a marginally significant association between circulating IGF-I levels and the risk of premenopausal breast cancer.     

Cancer risk factors associated with insulin-like growth factor (IGF)-I and IGF-binding protein-3 levels in healthy women: effect modification by menopausal status

Insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) appear to influence breast cancer risk and are hypothesized to mediate the effects of several cancer risk factors that depend on menopausal status. We investigated associations among cancer risk factors and plasma IGF-I and IGFBP-3 in 882 healthy control women (426 premenopausal, 456 postmenopausal) from two population-based breast cancer case–control studies. Interactions with menopausal status were statistically tested. We observed associations with non-modifiable (age, benign breast disease) and modifiable factors [body mass index (BMI), physical activity, smoking habits, alcohol consumption]. Furthermore, we demonstrated statistical interactions with menopausal status. Premenopausal IGFBP-3 levels increased and postmenopausal levels decreased with age (p-interaction = 0.001). Overweight postmenopausal women had higher IGF-I (p = 0.049) and IGFBP-3 (p = 0.005) levels than women with lower BMI. Postmenopausal IGF-I levels were positively associated with physical activity (p-trend = 0.012, p-interaction = 0.050). Postmenopausal current smokers had lower IGF-I (p = 0.014) and IGFBP-3 levels (p = 0.011). Increasing alcohol consumption was associated with lower premenopausal IGF-I (p-trend = 0.002, p-interaction = 0.004) and higher postmenopausal IGFBP-3 levels (p = 0.019). Benign breast disease was associated with higher premenopausal (p = 0.044) and postmenopausal (p = 0.002) IGF-I levels. IGF-I and/or IGFBP-3 potentially mediate changes in breast cancer risk associated with BMI, benign breast disease, and perhaps alcohol consumption. Other observed associations suggest that neither IGF-I nor IGFBP-3 alone acts as mediator. Consideration of menopausal status may help disentangle carcinogenic pathways involving IGF proteins.