Circulating levels of insulin-like growth factors, their binding proteins, and breast cancer risk.

BACKGROUND: Earlier data support the hypothesis that the relation between circulating insulin-like growth factor-I (IGF-I) levels and breast cancer risk differs by menopausal status. The strong association of IGF-I with height in childhood and weak or no association between adult levels and adult height also suggest that IGF levels in young women may better reflect an exposure time period of importance to breast cancer. Few studies have assessed IGF binding protein-1 (IGFBP-1) or free IGF and breast cancer risk. MATERIALS AND METHODS: We conducted a large case-control study nested within the prospective Nurses' Health Study. Plasma concentrations of IGF-I, free IGF, IGFBP-3, and IGFBP-1 were measured in blood samples collected in 1989 to 1990. Eight hundred women were identified who had a diagnosis of invasive or in situ breast cancer after blood collection, up to 1998, 27% of whom were premenopausal at blood collection. To those 800 women, one to two controls were age-matched for a total of 1,129 controls. We used logistic regression models to estimate the relative risk (RR) of breast cancer associated with IGF levels.Findings: Among postmenopausal women, neither IGF-I, IGFBP-3, IGFBP-1, nor free IGF was associated with breast cancer risk [RRs, top versus bottom quintile: IGF-I, 1.0; 95% confidence interval (95% CI), 0.7-1.4; IGFBP-3, 0.8; 95% CI, 0.6-1.1; IGFBP-1, 0.9; 95% CI, 0.6-1.5; and free IGF, 1.0; 95% CI, 0.6-1.4]. Among premenopausal women, IGFBP-3, IGFBP-1, and free IGF similarly were not associated with breast cancer risk (RRs, top versus bottom quintile: IGFBP-3, 1.2; 95% CI, 0.8-2.3; IGFBP-1, 1.5; 95% CI, 0.8-3.0; and free IGF, 1.1; 95% CI, 0.7-2.1). Higher IGF-I plasma levels, however, were associated with a modestly elevated breast cancer risk (RR, 1.6; 95% CI, 1.0-2.6) among the premenopausal women, with a stronger association among premenopausal women ages < or =50 (RR, 2.5; 95% CI, 1.4-4.3); further adjustment for IGFBP-3 did not greatly change these estimates. INTERPRETATION: Circulating IGF-I levels seem to be modestly associated with breast cancer risk among premenopausal women, but not among postmenopausal women. IGFBP-3, IGFBP-1, and free IGF are not associated with breast cancer risk in either premenopausal or postmenopausal women in this cohort.     

Premenopausal levels of circulating insulin-like growth factor I and the risk of postmenopausal breast cancer

Increased levels of insulin-like growth factor I (IGF-I) may directly stimulate breast cell proliferation and promote growth and survival of transformed cells. Higher levels of IGF-I have been associated with increased risk of premenopausal breast cancer but not postmenopausal breast cancer. We investigated whether circulating levels of IGF-I prior to menopause are associated with breast cancer diagnosed after menopause in a population-based nested case-control study. Female cohort participants were enrolled in 1974 (n = 15,192) and 1989 (n = 18,724) and blood was drawn. Cases were women diagnosed with primary breast cancer at ages > or =50, of whom 152 were premenopausal at blood draw. One control was matched to each case on cohort participation, age, ethnic group, menopausal status and date of blood draw. Levels of IGF-I and IGF binding protein 3 (IGFBP-3) were measured using enzyme-linked immunoabsorbent assays. The association between IGF-I and breast cancer was determined using conditional logistic regression, adjusting for IGFBP-3. IGF-I levels decreased with age (p = 0.0001). Prior to age-stratification, IGF-I levels neither measured before nor after menopause were associated with postmenopausal breast cancer. After age-stratification, associations were suggested in the youngest premenopausal age group (upper vs. lowest third: odds ratio (OR) = 5.31, 95% confidence intervals (CI) = 0.85-33.13; p trend = 0.06) and oldest postmenopausal age group (upper vs. lowest third: OR = 3.41, 95% CI = 0.66-17.71; p trend = 0.13). The association between circulating levels of IGF-I and postmenopausal breast cancer risk may be modified by age. Increased levels of circulating IGF-I may be of particular interest in the younger premenopausal women and older postmenopausal women. Age-stratification should be undertaken in larger investigations of IGF-I levels as predictors of postmenopausal breast cancer.     

Insulin-like growth factor I (IGF-I), IGF-binding proteins, and breast cancer.

Epidemiological evidence supports a role for the insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) in the induction and progression of various cancers. Estrogen, which plays a role in the etiology of breast cancer, both regulates and is influenced by the IGF family. Risk of breast cancer associated with serum levels of IGF-I and/or IGFBPs may therefore depend upon menopausal status. A nested, case-control study was conducted on 66 women who were premenopausal and 60 who were postmenopausal at the time of diagnosis of primary breast cancer; they were selected from a cohort of 95,000 women who underwent multiphasic health check-ups > 30 years ago when enrolled in the Kaiser Permanente Medical Care Program. For each case, one control who matched by age, date of examination, and length of follow-up was chosen. Concentrations of IGF-I, insulin, glucose, and IGFBP-1, IGFBP-2, and IGFBP-3 in serum drawn at least 2 years before diagnosis (mean times of 10.5 and 15.8 years for pre- and postmenopausal cases, respectively) were compared using conditional logistic regression analysis. All statistical tests were two-sided. Serum IGF-I, adjusted for insulin, glucose, and body mass index, was weakly associated with breast cancer risk across quartiles for premenopausal women only (P for trend = 0.05). Serum IGFBP-3 was higher in premenopausal cases versus controls (P = 0.04) and showed a positive trend in risk for increasing quartiles (P for trend = 0.033). After adjusting for insulin, glucose, body mass index, and IGF-I, premenopausal women in the highest quartile of IGFBP-3 had an elevated risk of breast cancer [odds ratio (OR) = 5.28, 95% confidence interval (CI) = 1.13-24.7]. Conversely, IGFBP-3 was lower in postmenopausal cases versus controls (P = 0.04) but showed no significant trend in risk. Postmenopausal women with glucose levels in the diabetic range were at increased risk for developing breast cancer (OR = 2.06, 95% CI = 0.87-4.91), whereas those in the highest quartile of IGFBP-2 had a substantial reduction (71%) in risk relative to those in the lowest quartile (OR = 0.29, 95% CI = 0.09-0.92). Serum IGFBP-1 was not associated with breast cancer risk in either pre- or postmenopausal women. In premenopausal women, elevated serum IGF-I and IGFBP-3 are associated with increased breast cancer risk, whereas elevated serum IGFBP-2 is inversely associated with risk of postmenopausal breast cancer.     

The insulin-like growth factor system and mammographic features in premenopausal and postmenopausal women.

High levels of circulating insulin-like growth factor-I (IGF-I) and its major binding protein (IGFBP-3) at premenopausal ages have been associated with an increased breast cancer risk. We conducted a cross-sectional study (215 premenopausal women and 241 after natural menopause) nested within the Guernsey prospective studies to examine the relationship between the IGF system and mammographic features of the breast. The mammographically dense area in the breast increased with increasing serum levels of IGF-I (P for linear trend, P(t) = 0.05), IGF-II (P(t) = 0.08), and IGFBP-3 (P(t) = 0.01) only in premenopausal women. IGF-II and IGFBP-3 serum levels were associated with increases in the mammographically lucent area in both premenopausal (P(t) = 0.01 and 0.04, respectively) and postmenopausal women (P(t) < 0.001 for both), but these associations were no longer statistically significant after adjustment for body mass index and waist circumference. Neither the IGF-I/IGFBP-3 nor the IGF-II/IGFBP-3 molar ratio was associated with any of these mammographic features. The number of A alleles at a polymorphic locus in the promoter region of the IGFBP-3 gene was associated with increasing mean IGFBP-3 levels in both premenopausal (P(t) = 0.01) and postmenopausal (P(t) <0.001) women but not with mammographically dense area. These results support the hypothesis that the IGF system may affect the amount of mammographically dense tissue in premenopausal women, possibly by promoting cell proliferation and inhibiting apoptosis in the fibroglandular tissue. The findings also show strong relations between IGF-II and IGFBP-3 levels and the amount of mammographically lucent tissue, reflecting the associations between body adiposity and amount of fat tissue in the breast and between body adiposity and circulating levels of these growth factors.     

Serum insulin-like growth factor-I and breast cancer

Insulin-like growth factor I (IGF-I) is a systemic hormone with potent mitogenic and anti-apoptotic properties, which could influence the proliferative behavior of normal breast cells. Limited epidemiological observations suggest that the hormone may play a role in the etiology of breast cancer, especially at pre-menopausal ages. In a prospective case-control study nested within a cohort of New York City women, IGF-I, IGF-binding protein 3 (IGFBP-3) and C peptide were measured in frozen serum samples from 172 pre-menopausal and 115 post-menopausal subjects who were subsequently diagnosed with breast cancer. Subjects were eligible if diagnosed 6 months or more after recruitment into the study (7 to 120 months). Cohort members who matched the cases on age, menopausal status, date of blood sampling and day of menstrual cycle at blood collection served as controls. Post-menopausal breast cancer was not associated with serum IGF-I, IGFBP-3 or C-peptide levels. However, the risk of breast cancer increased with increasing serum concentrations of IGF-I in pre-menopausal women. The odds ratio (OR) for the highest quartile of IGF-I (>256 ng/ml) compared to the lowest (<168 ng/ml) was 1.60 [95% confidence interval (CI) 0.91-2. 81]. The OR decreased to 1.49 (95% CI 0.80-2.79) after adjustment for IGFBP-3. In analyses restricted to subjects who were pre-menopausal at the time of blood sampling and whose cancer was diagnosed before age 50, the top vs. bottom quartile OR increased appreciably to 2.30 (95% CI 1.07-4.94). Adjustment for IGFBP-3 reduced the OR to 1.90 (95% CI 0.82-4.42). There was no association between pre-menopausal breast cancer and IGFBP-3, IGF-I:IGFBP-3 ratio or non-fasting levels of C peptide. Elevated circulating levels of IGF-I may be an indicator of increased risk of breast cancer occurring before age 50.     

IGF-I and breast cancer: a meta-analysis

IGFs are peptide hormones involved in the regulation of cell proliferation, differentiation and apoptosis. IGFs are regulated by endocrine and paracrine mechanisms; however, their action in tissue is determined by circulating levels and local production of IGFs and IGF-binding proteins (IGFBPs). Some, but not all, epidemiologic studies have associated high circulating levels of IGF-I with increased risk of breast cancer among premenopausal women. To evaluate the overall association of IGF-I and IGFBP-3 levels with breast cancer risk, we performed a meta-analysis on 16 publications of epidemiologic and clinical studies. Analyses were performed for all women as well as for pre- and postmenopausal women separately. Hedges' standardized mean differences (HSMDs) and odds ratios (ORs) were used to estimate the effect of IGF-I and IGFBP-3. Data analysis showed that circulating levels of IGF-I were not significantly higher in breast cancer patients than in controls for all women and for the postmenopausal group (HSMD = 0.024 and 0.035, respectively; p > 0.40) but were significantly higher (HSMD = 0.170, p < 0.001) for the premenopausal group. ORs for breast cancer risk were 1.05 (95% CI 0.94-1.17), 0.93 (95% CI 0.80-1.10) and 1.39 (95% CI 1.16-1.66). The HSMD of IGFBP-3 was 0.18 (p < 0.001), and the OR for breast cancer was 1.42 (95% CI 1.15-1.74) for premenopausal women. Our results support the suggested association between high IGF-I and IGFBP-3 levels and increased risk of breast cancer in premenopausal women.     

Insulin-like growth factor-I, IGF binding protein-3, and breast cancer in young women: a comparison of risk estimates using different peptide assays.

Circulating insulin-like growth factor-I (IGF-I) and its major binding protein IGF binding protein-3 (IGFBP-3) have been associated with increased risk of premenopausal breast cancer, although risk estimates varied broadly. An extension of a case-control study (138 cases, 259 matched controls) on IGF-I and breast cancer in premenopausal women nested in the New York University Women's Health Study cohort offered the opportunity to address the hypothesis that such variability may have been the result of variations in the ability of different IGFBP-3 assays to specifically measure intact/functional forms of the protein. IGF-I and IGFBP-3 had originally been measured using in-house RIAs. These measurements were repeated using commercially available ELISAs [Diagnostic System Laboratories (DSL), Webster, Texas], and a third ELISA with greater specificity for active forms for IGFBP-3. Pearson's correlations between IGF-I concentrations in the original study and DSL ELISA were very high [r = 0.92; 95% CI, 0.90-0.94]. Correlations with DSL ELISA were much lower for IGFBP-3 (r = 0.58; 0.49-0.66) and even lower still with the assay for functional IGFBP-3 (r = 0.33; 0.20-0.44). IGF-I and IGFBP-3 measurements by the DSL ELISA methods showed statistically significant relationships with risk. The odds ratios (OR) for top versus bottom quartiles were 1.93 (1.00-3.72; P = 0.02) and 2.03 (1.09-3.76; P = 0.02), respectively, in agreement with the original observations. In contrast, measurements of functional IGFBP-3 tended to be unrelated to risk [ORs for the top versus bottom quartile, 0.97 (0.44-2.11)]. The association with IGF-I became substantially weaker and lost statistical significance after adjustment for IGFBP-3 using DSL ELISA, but became considerably stronger when adjusting for the functional IGFBP-3 measurements [OR = 2.43 (1.21-4.90); P = 0.005], or when considering the molar ratio of IGF-I to IGFBP-3 [OR = 2.37 (1.13-5.00); P = 0.02]. These results are consistent with an association of breast cancer risk in young women with elevated IGF-I and IGFBP-3, and show that for IGFBP-3, the strength of such an association could vary substantially depending on the assay used.     

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.     

Circulating levels of insulin-like growth factor I,its binding proteins -1,-2, -3, C-peptide and risk of postmenopausal breast cancer

Higher levels of circulating Insulin-like Growth Factor (IGF)-I may be associated with higher risks for premenopausal breast cancer. We investigate the associations between circulating levels of IGF-I, its binding proteins (IGFBPs) -1, -2, -3, C-peptide and postmenopausal breast cancer. This is a prospective study nested in 2 Dutch cohorts. The study population included women who were postmenopausal at baseline. Breast cancer cases were identified through linkage with cancer registries. Controls were matched to cases by cohort, age, date of blood donation and place of residence. In total, 149 breast cancer cases and 333 healthy controls were included. Plasma levels of IGF-I, IGFBP-1, -2, -3 and C-peptide were measured by radioimmunoassays. Estimates of the relative risk for breast cancer associated with the quartiles of the peptides' circulating levels were obtained by conditional logistic regression. Models were adjusted for BMI, age at menarche and age at first full-term delivery. For IGF-I, the adjusted OR (95% CI) of the top vs. bottom quartile was 1.1 (0.6; 2.1); for IGFBP-1 it was 0.7 (0.3; 1.3); for IGFBP-2, 1.1 (0.5; 2.4); for IGFBP-3, 1.6 (0.7; 3.5), for C-peptide, 1.3 (0.7; 2.7) and for IGF-I/IGFBP-3 ratio, 1.0 (0.5; 1.8). Our data do not support an association between postmenopausal circulating levels of IGF-I, IGFBP-1, -2, -3, C-peptide and postmenopausal breast cancer.     

Plasma insulin-like growth factor (IGF) I, IGF-binding protein 3, and mammographic density

Insulin-like growth factors (IGFs) and insulin-like growth factor-binding proteins (IGFBPs) play a role in the normal development of breast tissue and possibly in the etiology of breast cancer. Breast density is one of the strongest predictors of breast cancer. In a cross-sectional analysis within the Nurses' Health Study, we compared the associations of plasma levels of endogenous IGF-I and IGFBP-3 with breast density in 65 premenopausal and 192 postmenopausal women. The digitized film screen mammograms were evaluated by the computer-assisted Toronto method, in which visually selected gray-scale cut points are used to assess breast density. Generalized linear models and Spearman's partial correlation coefficients described the associations between breast density and IGF-I, IGFBP-3, and the IGF-I:IGFBP-3 ratio. Premenopausal breast density was positively correlated with IGF-I and inversely correlated with IGFBP-3; the association was strongest for the IGF-I:IGFBP-3 ratio and breast density (r = 0.39; P = 0.004). In contrast, the correlation between breast density and the IGF-I:IGFBP-3 ratio among postmenopausal women was -0.02 (P = 0.83). The associations of IGF-I:IGFBP-3 ratio with breast density differed significantly between premenopausal and postmenopausal women (P = 0.01). Mammographic density is positively associated with plasma IGF-I levels and inversely associated with plasma IGFBP-3 levels among premenopausal women, but not among postmenopausal women. These results are consistent with previous studies that showed a positive association between a higher IGF-I:IGFBP-3 ratio and subsequent risk of breast cancer only among premenopausal women. The findings raise the possibility that premenopausal levels of IGF-I and IGFBP-3 could be in the etiological pathway that relates higher breast density with increased breast cancer risk.     

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.

Elevated insulin-like growth factor I (IGF-I) is associated with an increased risk for developing breast cancer in premenopausal women, whereas lower leptin levels have been documented in premenopausal breast cancer cases. We determined the effect of raloxifene on IGF-I, insulin-like growth factor binding protein 3 (IGFBP-3), and leptin in premenopausal women at high risk for developing invasive breast cancer. Twenty-eight premenopausal women (median age 43 years) participating in a pilot breast cancer prevention trial provided 56 matched serum samples. Specimens were collected at baseline and after treatment with 60 mg of raloxifene daily. Median treatment duration was 3 months (range: 6 weeks to 12 months). Samples were frozen at -70 degrees C until analysis. IGF-I, IGFBP-3, and leptin were measured by ELISA. Significance was evaluated by the Wilcoxon signed rank test. Raloxifene administration increased serum IGFBP-3 [mean change 245 ng/ml; P = 0.017; 95% confidence interval (CI), 76-415] and leptin (mean change 2.1 ng/ml; P = 0.005; 95% CI, 0.6-3.7). No significant change in serum IGF-I was detected (mean change 2.6 ng/ml; P = 0.84; 95% CI, -15.4 to 20.6). IGF-I:IGFBP-3 molar ratio was stable (mean change -0.014; P = 0.30; 95% CI, -0.041 to 0.012). Raloxifene administration is associated with an increase in IGFBP-3 and leptin in premenopausal high risk women. Increases in IGFBP-3 may potentially decrease the activity of circulating IGF-I. The effect of modulating the IGF pathway and leptin on breast cancer risk needs additional evaluation.     

Circulating insulin-like growth factor-I and binding protein-3 and the risk of breast cancer.

Four meta-analyses and literature reviews have concluded that a positive association exists between circulating levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) and breast cancer risk for premenopausal but not postmenopausal women. Recently, a large prospective study reported an association with IGF-I and IGFBP-3 concentration for breast cancer diagnosed after, but not before, the age of 50 years; and in a large cohort of primarily premenopausal women, IGF-I and IGFBP-3 were not associated with breast cancer risk. We did a case-cohort study within the Melbourne Collaborative Cohort Study, which included a random sample of 1,901 women (subcohort) and 423 breast cancer cases diagnosed during a mean of 9.1 years of follow-up. IGF-I and IGFBP-3 concentrations were measured in plasma collected at baseline. The association between quartiles of IGF concentration and breast cancer risk was tested using a Cox model adjusted for known and potential confounders. The hazard ratio (HR) for breast cancer comparing the fourth with the first quartiles was 1.20 [95% confidence interval (95% CI), 0.87-1.65] for IGF-I and 1.09 (95% CI, 0.78-1.53) for IGFBP-3. Both associations varied with age: for IGF-I, the HRs for breast cancer comparing the fourth with the first quartiles were 0.60 (95% CI, 0.25-1.45) before age 50 and 1.61 (95% CI, 1.04-2.51) after age 60 (test for the log-linear trend of HR according to age, P = 0.05); for IGFBP-3, the HRs were 0.79 (95% CI, 0.34-1.83) before age 50 and 1.62 (95% CI, 1.03-2.55) after age 60 (test for log-linear trend, P = 0.08). IGF-I and IGFBP-3 were positively associated with breast cancer risk in older women but not in younger women. More prospective studies are needed to clarify the age dependence of the association between IGF-I and IGFBP-3 and breast cancer.     

Circulating Insulin-like Growth Factor (IGF)-I and IGF Binding Protein (IGFBP)-3 Levels and Postmenopausal Breast Cancer Risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) Cohort

Early prospective studies suggested circulating insulin-like growth factor (IGF)-I was positively associated with risk of premenopausal, but not postmenopausal, breast cancer; however, a recent, large analysis reported a statistically significant positive association with postmenopausal disease. Therefore, we conducted a large study nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort to assess the association between circulating IGF-I and IGF binding protein (IGFBP)-3 levels and subsequent postmenopausal breast cancer risk. We included 389 breast cancer cases and 470 controls, aged 55-74, not using exogenous hormones at blood draw, and matched by age at and date of serum collection. Mean follow-up was 8.5 years; mean time between serum collection and diagnosis was 4.0 years. We used Cox proportional hazards regression models to obtain hazard ratios (HRs) and 95% confidence intervals (95% CIs). Multivariate HRs for IGF-I, IGFBP-3, and the molar ratio IGF-I/IGFBP-3, comparing the highest quintile to the lowest, were 1.28 (95% CI, 0.67-2.44), 1.12 (95% 0.55-2.27), and 1.25 (95% 0.72-2.15), respectively. Multivariate HRs per one quintile increase were 1.07 (95% 0.92-1.25) for IGF-I, 1.01 (95% 0.86-1.18) for IGFBP-3, and 1.10 (95% 0.98-1.24) for the molar ratio. These models included accepted breast cancer risk factors and height, along with baseline BMI and serum estradiol, both of which increased the risk associated with IGF-I and the molar ratio. IGF-I and the IGF-I/IGFBP-3 molar ratio were positively, although not statistically significantly, associated with postmenopausal breast cancer risk. Further research should emphasize larger studies, including pooled analyses, analyses by cancer subtype, improved exposure assessment, and possible mechanisms.     

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.

PURPOSE: High circulating insulin-like growth factor (IGF) -I and/or low IGF-binding protein (IGFBP) -3 levels are associated with increased breast cancer risk in unaffected premenopausal women. We determined whether IGF-I and IGFBP-3 predict second breast cancer risk, and whether their changes during fenretinide explain observed reductions in second breast cancer in women 相似文献   

Insulin and related factors in premenopausal breast cancer risk

Background: Insulin and insulin-like growth factor I (IGF-I) are important mitogens in vitro and in vivo. It has been hypothesized that these factors may play an important role in the development of breast cancer. Methods: A case-control study comparing plasma insulin levels in 99 premenopausal women with newly diagnosed node-negative invasive carcinoma of the breast and 99 age-matched controls with incident biopsied non-proliferative breast disease (NP) was conducted. Women with known diabetes were excluded. Results: For the entire study group, mean age was 42.6 ± 5.1 years and mean weight was 62.9 ± 10.3 kg. After adjustment for age and weight, elevated insulin levels were significantly associated with breast cancer, Odds Ratio (OR) for women in the highest insulin quintile versus the lowest quintile=2.83 (95% Confidence Interval [CI] 1.22–6.58). There were no statistically significant differences between cases and controls for IGF-I and IGFBP-1 levels. However, after adjustment for age, the association between plasma levels of insulin-like growth factor binding protein 3 (IGFBP-3) and breast cancer approached statistical significance; OR for highest quintile versus lowest quintile of IGFBP-3 being 2.05 (95% CI, 0.93–4.53). All results were independent of diet and other known risk factors for breast cancer. Conclusion: Circulating insulin levels and possibly IGFBP-3 levels are elevated in women with premenopausal breast cancer. This association may reflect an underlying syndrome of insulin resistance that is independent of obesity.     

Serum Insulin-like Growth Factors, Insulin-like Growth Factor-binding Protein-3, and Risk of Lung Cancer Death: A Case-control Study Nested in the Japan Collaborative Cohort (JACC) Study

To elucidate the roles of insulin-like growth factors (IGFs) in the development of lung cancer, we conducted a case-control study nested within the Japan Collaborative Cohort Study. Serum samples were collected at baseline from 39 140 men and women between 1988 and 1990. We measured serum IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) in 194 case subjects who subsequently died from lung cancer during an 8-year follow-up and in 9351 controls. The odds ratios (ORs), adjusted for smoking and other covariates, were smaller with higher levels of IGF-II and IGFBP-3. The ORs across quartiles were 0.41 (95% confidence interval [CI], 0.27–0.63), 0.47 (0.31–0.71), and 0.67 (0.46–0.98) for IGF-II (trend P =0.018), and 0.55 (95% CI, 0.37–0.81), 0.54 (0.36–0.82), and 0.67 (0.45–1.01) for IGFBP-3 (trend P =0.037). These peptides were not independently related to lung cancer risk when mutually adjusted. The risk was increased in the highest vs. the lowest quartile of IGF-I only after controlling for IGFBP-3 (OR, 1.74; 95% CI, 1.08–2.81). Limiting subjects to those followed for ≥3 years strengthened the negative associations of IGF-II and IGFBP-3, whereas the ORs for IGF-I generally decreased. A higher level of circulating IGFBP-3 and/or IGF-II may decrease lung cancer risk. Elevated serum IGF-I may increase the risk, but this could partly be attributable to latent tumors.     

Serum insulin-like growth factors, insulin-like growth factor-binding protein-3, and risk of lung cancer death: a case-control study nested in the Japan Collaborative Cohort (JACC) Study.

To elucidate the roles of insulin-like growth factors (IGFs) in the development of lung cancer, we conducted a case-control study nested within the Japan Collaborative Cohort Study. Serum samples were collected at baseline from 39140 men and women between 1988 and 1990. We measured serum IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) in 194 case subjects who subsequently died from lung cancer during an 8-year follow-up and in 9351 controls. The odds ratios (ORs), adjusted for smoking and other covariates, were smaller with higher levels of IGF-II and IGFBP-3. The ORs across quartiles were 0.41 (95% confidence interval [CI], 0.27-0.63), 0.47 (0.31-0.71), and 0.67 (0.46-0.98) for IGF-II (trend P=0.018), and 0.55 (95% CI, 0.37-0.81), 0.54 (0.36-0.82), and 0.67 (0.45-1.01) for IGFBP-3 (trend P=0.037). These peptides were not independently related to lung cancer risk when mutually adjusted. The risk was increased in the highest vs. the lowest quartile of IGF-I only after controlling for IGFBP-3 (OR, 1.74; 95% CI, 1.08-2.81). Limiting subjects to those followed for 3 years strengthened the negative associations of IGF-II and IGFBP-3, whereas the ORs for IGF-I generally decreased. A higher level of circulating IGFBP-3 and / or IGF-II may decrease lung cancer risk. Elevated serum IGF-I may increase the risk, but this could partly be attributable to latent tumors.     

High levels of circulating insulin-like growth factor-I increase prostate cancer risk: a prospective study in a population-based nonscreened cohort.

PURPOSE: Insulin-like growth factor-I (IGF-I) stimulates proliferation and inhibits apoptosis in prostate cancer cells, and IGF-I has been associated with increased prostate cancer risk in some, but not all, epidemiologic studies. SUBJECTS AND METHODS: We extended our previous case-control study nested in the Northern Sweden Health and Disease Cohort, a population-based cohort from a region where little prostate specific antigen (PSA) screening is done. Levels of IGF-I and IGF binding protein-3 (IGFBP-3) were measured in prediagnostic blood samples from a total of 281 men who were subsequently diagnosed with prostate cancer after recruitment (median, 5 years after blood collection) and from 560 matched controls. RESULTS: Logistic regression analyses showed increases in prostate cancer risk with increasing plasma peptide levels, up to an odds ratio (OR) for top versus bottom quartile of IGF-I of 1.67 (95% CI, 1.02 to 2.71; Ptrend = .05), which was attenuated after adjustment for IGFBP-3 to an OR of 1.47 (95% CI, 0.81 to 2.64; P (trend) =.32). For men younger than 59 years at recruitment, OR for top versus bottom quartile of IGF-I was 4.12 (95% CI, 1.01 to 16.70; Ptrend = .002), which was significantly stronger than for men older than 59 years (P (interaction) = .006). For men with advanced cancer, OR for top versus bottom quartile of IGF-I was 2.87 (95% CI, 1.01 to 8.12; Ptrend = .10). CONCLUSION: Our data add further support for IGF-I as an etiologic factor in prostate cancer and indicate that circulating IGF-I levels measured at a comparatively young age may be most strongly associated with prostate cancer risk.     

Long-term effects of fenretinide, a retinoic acid derivative, on the insulin-like growth factor system in women with early breast cancer.

High insulin-like growth factor-I (IGF-I) levels are associated with an increased risk of breast cancer in premenopausal women. Because the synthetic retinoid fenretinide showed a beneficial effect on second breast cancers in premenopausal women in a Phase III trial, we studied its long-term effects on IGF-I levels. We measured, at yearly intervals for up to 5 years, the circulating levels of IGF-I, IGF binding protein (BP)-3, and their molar ratio in 60 subjects < or = 50 years of age and 60 subjects > 50 years of age allocated either to fenretinide or no treatment. In women < or = 50 years of age, measurements of IGF-II, IGFBP-1, and IGFBP-2 were also performed. The associations between biomarkers and drug or metabolite plasma concentrations were also investigated. All biomarkers were relatively stable over 5 years in the control group. Compared with controls and after adjustment for baseline, treatment with fenretinide for 1 year induced the following changes: IGF-I, -13% [95% confidence interval (CI), -25 to 1%] in women < or = 50 years of age and -3% (95% CI, -16 to 13%) in women > 50 years of age; IGFBP-3, -4% (95% CI, -12 to 6%) in both age groups; IGF-I:IGFBP-3 molar ratio, -11% (95% CI, -22 to 1%) in women < or = 50 years of age and 1% (95% CI, -11 to 16%) in women > 50 years of age. These effects were apparently maintained for up to 5 years, although fewer samples were available as time progressed. No change in other IGF components was observed. Drug and metabolite concentrations were negatively correlated with IGF-I and IGF-I:IGFBP-3 molar ratio in women < or = 50 years of age. Fenretinide induces a moderate decline of IGF-I levels in women < or = 50 years of age. The association between IGF-I change and the reduction of second breast cancers in premenopausal women warrants further study.     

Insulin-like growth factors and breast cancer risk in Chinese women.

Insulin-like growth factor (IGF)-I has mitogenic and antiapoptotic effects on breast cancer cells. High-circulating IGF-I was found to be associated with increased risk of breast cancer in several previous epidemiological studies, mostly conducted in the Caucasian populations. Little is known about the association between IGF and breast cancer in Asian women whose dietary habits differ considerably from their Caucasian counterparts. A population-based case-control study was conducted to assess the associations of IGFs and IGF binding protein-3, a major IGF binding protein in the circulation, with breast cancer risk in Chinese women. The study included 300 incident breast cancer patients diagnosed between August 1996 and March 1998 in Shanghai and 300 age- and menopause-matched controls selected randomly from the general population. Plasma levels of IGF-I, IGF-II, and IGFBP-3 were measured using commercial ELISA kits (Diagnostic Systems Laboratories, Webster, TX). Conditional logistic regression analysis was performed to examine the association between IGF and breast cancer risk after adjusting for potential confounding factors. Breast cancer patients had higher plasma levels of IGF-I and IGFBP-3. A dose-response relationship was observed between breast cancer risk and the level of IGF-I or IGFBP-3. The adjusted odds ratios were 2.01 (95% confidence interval, 1.26-3.19) or 3.01 (95% confidence interval, 1.81-4.99), respectively, for women with the highest tertile of IGF-I or IGFBP-3 compared with those with the lowest tertile of these molecules. These associations were more evident in premenopausal women or women with high body mass index or high waist-to-hip ratio. No significant association was found for IGF-II. The study confirms that high circulating levels of IGF-I are associated with elevated risk of breast cancer. In contrast to the findings from several studies conducted in Caucasian women, we found that IGFBP-3 was positively associated with breast cancer risk in Chinese women.