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.     

Determinants of circulating insulin-like growth factor (IGF)-I and IGF binding proteins 1–3 in premenopausal women: physical activity and anthropometry (Netherlands)

Objective: Epidemiologic studies suggest that subjects with elevated plasma concentrations of IGF-I are at increased risk of developing cancer. The objective of our study was to assess whether cancer risk factors such as lack of physical activity, obesity, and central body fat distribution are associated with plasma levels of IGF-I and related proteins (i.e. IGF binding proteins 1–3 and C-peptide). Methods: A cross-sectional study was conducted in a population of 225 premenopausal women, aged 49–57, participating in the Prospect–EPIC study in the Netherlands. Plasma concentrations of IGF-I, IGFBP-1, IGFBP-2, IGFBP-3, and C-peptide were determined. On the day of blood collection height, weight, and waist and hip circumference were measured. Habitual physical activity was assessed using a validated self-administered questionnaire. Results: Mean concentrations of plasma IGF-I, IGFBP-1, IGFBP-2, IGFBP-3, and C-peptide were 156.1, 14.3, 434.4, 3062, and 2.86 ng/ml, respectively. Women in the highest tertile for physical activity had lower plasma concentrations of IGF-I, IGFBP-3, and C-peptide, and higher concentrations of IGFBP-1 and IGFBP-2, as compared to women in the lowest tertile. However, these differences were not statistically significant. BMI and related measures were significantly inversely associated with IGFBP-1 and IGFBP-2, and positively with IGFBP-3 and C-peptide. Linear regression analyses showed that the non-significant association of physical activity with components of the plasma IGF system was further attenuated by adjusting for obesity and central body fat distribution. Conclusions: Our data suggest that an active lifestyle is not independently associated with the plasma IGF system. We did confirm that a lean body shape is associated with higher concentrations of IGFBP-1 and IGFBP-2, and possibly also with lower concentrations of IGF-I and IGFBP-3.     

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.     

A prospective study of serum insulin-like growth factor-I (IGF-I), IGF-II, IGF-binding protein-3 and breast cancer risk

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.     

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.     

Determinants of circulating insulin-like growth factor I and insulin-like growth factor binding protein 3 concentrations in a cohort of Singapore men and women.

Variation in the circulating concentrations of the insulin-like growth factor (IGF) system has been implicated in the etiology of chronic diseases including cancer (prostate, breast, colon, and lung), heart disease, type 2 diabetes, and osteoporosis. We searched for sociodemographic, anthropometric, reproductive, lifestyle, and dietary determinants of IGF-I and insulin-like growth factor binding protein (IGFBP) -3 serum concentrations. Serum samples were collected in a Singapore Chinese cohort with a mean age of 61 years. Subject information was assessed during an in-person interview. Radioimmunometrically measured IGF-I and IGFBP-3 concentrations were available for 312 men and 326 postmenopausal women ages 50 years or older. Mean IGF-I concentrations were 144 ng/ml and 121 ng/ml for men and women, respectively (gender difference, P < 0.0001), and mean IGFBP-3 concentrations were 3710 ng/ml and 4147 ng/ml for men and women, respectively (gender difference, P < 0.0001). IGF-I and IGFBP-3 decreased with age (P for trend <0.0001); the age-related decrease in the IGF-I:IGFBP-3 molar ratio was stronger in women than men. IGF-I concentrations were higher among physically inactive subjects and among women with an early age at menarche. Consumption of saturated fat was found to decrease, and intake of omega-3 polyunsaturated fatty acids and of dietary fiber was found to increase circulating IGFBP-3 concentrations. Intake of calcium from food and supplement was associated positively with circulating IGF-I, IGFBP-3, and molar ratio. Intake of soy was associated positively with IGF-I and molar ratio concentrations, but only in men. The results of this study lend additional support to the hypothesis that circulating IGF-I concentrations increase the risk of prostate, bladder, colorectal, and breast cancer.     

Plasma enterolactone and genistein and the risk of premenopausal breast cancer.

BACKGROUND: The scientific debate on the role of dietary phytoestrogens for prevention of breast cancer is still ongoing. We previously reported an inverse association between dietary phytoestrogen intake and premenopausal breast cancer risk and now examine the relationship with plasma phytoestrogen concentrations. METHODS: We measured enterolactone (mammalian lignan) and genistein (isoflavone) concentrations in plasma samples of 220 premenopausal cases and 237 age-matched controls from a population-based case-control study in Germany. RESULTS: Median plasma enterolactone concentrations in cases and controls were 6.3 and 9.7 nmol/l, respectively, and median genistein concentrations were 4.5 and 3.7 nmol/l, respectively. Premenopausal breast cancer risk decreased with increasing plasma enterolactone concentrations. Adjusted odds ratios (95% confidence intervals) were 0.42 (0.20-0.90) and 0.38 (0.17-0.85) (P for trend 0.007) for women in the third and fourth quartile of plasma enterolactone compared to those in the lowest quartile. There was no significant association between plasma genistein concentration and premenopausal breast cancer risk. CONCLUSION: Using biomarkers of phytoestrogen intake, we confirmed the strong inverse association between enterolactone and premenopausal breast cancer risk as found with dietary intake estimates. This result gives support to the potential role of mammalian lignans for breast cancer prevention among premenopausal women in Western populations.     

Dietary Fat, Fiber, and Carbohydrate Intake and Endogenous Hormone Levels in Premenopausal Women

The authors conducted a cross-sectional study to investigate the associations of fat, fiber, and carbohydrate intake with endogenous estrogen, androgen, and insulin-like growth factor (IGF) levels among 595 premenopausal women. Overall, no significant associations were found between dietary intake of these macronutrients and plasma sex steroid hormone levels. Dietary fat intake was inversely associated with IGF-I and IGF-binding protein 3 (IGFBP-3) levels. When substituting 5% of energy from total fat for the equivalent amount of energy from carbohydrate or protein intake, the plasma levels of IGF-I and IGFBP-3 were 2.8% (95% confidence interval [CI] 0.3, 5.3) and 1.6% (95% CI 0.4, 2.8) lower, respectively. Animal fat, saturated fat, and monounsaturated fat intakes also were inversely associated with IGFBP-3 levels (P<0.05). Carbohydrates were positively associated with plasma IGF-I level. When substituting 5% of energy from carbohydrates for the equivalent amount of energy from fat or protein intake, the plasma IGF-I level was 2.0% (95% CI 0.1, 3.9%) higher. No independent associations between fiber intake and hormone levels were observed. The results suggest that a low-fat/high-fiber or carbohydrate diet is not associated with endogenous levels of sex steroid hormones, but it may modestly increase IGF-I and IGFBP-3 levels among premenopausal women.     

Dietary phytoestrogen intake and premenopausal breast cancer risk in a German case-control study

A diet high in isoflavonoids (soy) is associated with lower breast cancer risk in Asian populations. Due to the low soy intake, dietary lignans may be the more important phytoestrogen class in Western populations. We used a population-based case-control study of breast cancer by age 50 in southern Germany to evaluate the association between dietary intake of different phytoestrogens and premenopausal breast cancer risk. Dietary information was collected from 278 premenopausal cases and 666 age-matched controls, using a validated FFQ. Using multivariate logistic regression, the highest vs. lowest intake quartiles of daidzein and genistein yielded significantly reduced ORs (95% CI) for breast cancer risk of 0.62 (0.40-0.95) and 0.47 (0.29-0.74), respectively. The protective effects of daidzein and genistein were found only for hormone receptor-positive tumors. High intake of other isoflavonoids, e.g., formononetin and biochanin A, as well as the sum of isoflavonoids were not associated with a decrease in risk. Breast cancer risk significantly decreased with a high intake of the plant lignan matairesinol (OR = 0.58, 95% CI 0.37-0.94) but not secoisolariciresinol or the sum of plant lignans. However, both estimated mammalian lignans, enterodiol and enterolactone, were inversely associated with breast cancer risk, with ORs (95% CI) of 0.61 (0.39-0.98) and 0.57 (0.35-0.92), respectively. No effect was found for total phytoestrogen intake. Our results suggest an important role of dietary intake of daidzein and genistein, despite low levels, as well as of matairesinol and mammalian lignans to reduce premenopausal breast cancer risk in this study population.     

Effects of tomato- and soy-rich diets on the IGF-I hormonal network: a crossover study of postmenopausal women at high risk for breast cancer

To determine whether dietary modifications with tomato products and/or a soy supplement affected circulating levels of insulin-like growth factor (IGF)-1 and other markers of cell signaling in postmenopausal women at risk for developing breast cancer. Eligible and consented postmenopausal women at high risk for developing breast cancer were enrolled in a 26-week, two-arm (tomato and soy, 10 weeks each) longitudinal dietary intervention study in which each woman served as her own control. Changes in biochemical endpoints including IGF-I, IGF-binding protein (IGFBP)-3, estradiol, sex hormone-binding globulin (SHBG), C-peptide, and insulin were measured for each intervention arm. Carotenoid and isoflavone levels were measured to assess adherence. Significant increases in carotenoid and isoflavone levels during the tomato and soy study arms, respectively, suggested that women were adherent to both arms of the intervention. The tomato-rich diet had little effect on cell-signaling biomarkers previously associated with breast cancer risk. However, results of the soy intervention showed that concentrations of IGF-I and IGFBP-3 increased by 21.6 and 154.7 μmol/L, respectively (P = 0.001 for both) and SHBG decreased by 5.4 μmol/L (P < 0.001) after consumption of the soy protein supplement. Increased soy protein intake may lead to small, but significant, increases in IGF-I and IGFBP-3. Soy consumption also led to a significant decrease in SHBG, which has been hypothesized to promote, rather than prevent, cancer growth. Previous epidemiologic studies, however, have confirmed protective effect of soy on breast cancer. Additional investigation about the effect of soy on breast cancer risk and its mechanism of action is warranted.     

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.     

Longitudinal associations of age, anthropometric and lifestyle factors with serum total insulin-like growth factor-I and IGF binding protein-3 levels in Black and White men: the CARDIA Male Hormone Study.

Although several studies have assessed cross-sectional correlates of serum insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3), there are no longitudinal studies of the correlates of long-term changes in these measures. We examined the 8-year longitudinal associations of age, body mass index (BMI), waist circumference, physical activity, number of cigarettes smoked per day, and alcohol intake with serum total IGF-I and IGFBP-3 concentrations in 622 Black and 796 White male participants of the Coronary Artery Risk Development in Young Adults Study who were ages 20 to 34 years at the time of the first IGF measurement. In generalized estimating equation analyses, IGF-I decreased by 5.6 and 5.9 ng/mL per year increase in age for Black and White men, respectively (P< 0.0001), and there was an age-related decline in IGFBP-3 that was stronger in Whites (P < 0.0001) than Blacks (P = 0.21). Average IGF-I (beta = -17.51 ng/mL) and IGFBP-3 (beta = -355.4 ng/mL) levels across all three exams were lower in Blacks than Whites (P < 0.0001). Increased BMI was associated with decreased IGF-I (P < 0.0002), but was not associated with IGFBP-3. There were no meaningful associations with waist circumference. Increased physical activity was associated with a decrease in IGFBP-3 (P < 0.05), but was not associated with IGF-I. In White men, there were weak inverse associations between the number of cigarettes smoked per day with IGF-I (P=0.15) and with IGFBP-3 (P = 0.19), and in Black men, increased alcohol intake was associated with a decrease in IGF-I (P = 0.011). In conclusion, these results support an age-related decline and Black-White difference in serum IGF-I and IGFBP-3 levels. Importantly, they suggest that IGF-I and/or IGFBP-3 levels could be influenced by changes in BMI, and perhaps by physical activity, alcohol intake, and cigarette smoking.     

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.     

Phytoestrogen exposure is associated with circulating sex hormone levels in postmenopausal women and interact with ESR1 and NR1I2 gene variants.

In this large cross-sectional study, we investigated the relationship between phytoestrogen exposure and circulating sex hormones and sex hormone-binding globulin (SHBG) levels in 1988 healthy postmenopausal women and their interactions with polymorphisms in genes involved in estrogen signaling. Plasma estradiol, testosterone, androstenedione, estrone, and SHBG were measured. Urinary levels of five isoflavones (daidzein, genistein, glycitein, O-desmethylangolensin, and equol) and two lignans (enterodiol and enterolactone) were measured and used as biomarkers for dietary intakes. Eighteen polymorphisms in ESR1, ESR2, and NR1I2 genes were genotyped. Results showed that lignans were positively associated with plasma SHBG levels (eta(p)(2) = 1.2%; P < 0.001) and negatively associated with plasma testosterone (eta(p)(2) = 0.2%; P = 0.042). Equol was negatively associated with plasma estradiol levels (eta(p)(2) = 0.3%; P = 0.028), whereas O-desmethylangolensin was positively associated with plasma estradiol level (eta(p)(2) = 0.3%; P = 0.010). There were significant phytoestrogen interactions with polymorphisms in ESR1 and NR1I2 genes in affecting estrone levels. We conclude that phytoestrogens modulate sex hormone and SHBG levels in postmenopausal women and interact with gene variants involved in estrogen signaling. Such phytoestrogen-gene interactions may explain the conflicting literature on the hormonal effects of phytoestrogens.     

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.     

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.     

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.     

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.     

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.     

Effects of alcohol and menstrual cycle on insulin-like growth factor-I and insulin-like growth factor binding protein-3.

Alcohol ingestion and insulin-like growth factor-I (IGF-I) have been associated with increased breast cancer risk, the latter primarily in premenopausal women. We investigated whether alcohol ingestion altered IGF-I or its major binding protein (BP), IGFBP-3, in a controlled feeding study in premenopausal women. We also determined whether IGF-I or IGFBP-3 was affected by menstrual cycle phase. Serum was collected from 31 individuals who were randomly assigned to consume either 0 or 30 g (two drinks) of alcohol daily for three menstrual cycles and who then crossed over to the other alcohol level for three cycles. All calories were provided and weight was maintained during the study. For both alcohol levels, serum was collected during the final cycle at early follicular, periovulatory, and luteal phases. Relative to the follicular phase, IGF-I levels increased by 3.3% and 7.6% in the periovulatory and luteal phases, respectively (P for trend = 0.004). Although alcohol ingestion did not affect this increase, it significantly reduced IGF-I concentrations at all phases (9.5%; P < 0.001), whereas IGFBP-3 was unaffected by either menstrual phase or alcohol. This is the first controlled diet study to show that alcohol decreases serum IGF-I in premenopausal women and that IGF-I significantly increases over the course of the menstrual cycle whether or not alcohol is present.