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.     

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.     

Insulin-like growth factor I in pregnancy and maternal risk of breast cancer.

BACKGROUND: The role of insulin-like growth factor (IGF)-I in breast cancer remains controversial, despite numerous reports on the association of the hormone with breast cancer or high-risk mammographic densities. We hypothesized that exposure to elevated IGF-I during early pregnancy, a period characterized by intense cell proliferation in the breasts and in the presence of high concentrations of sex steroids, will be associated with increased maternal risk to develop a breast malignancy. METHODS: The Northern Sweden Maternity Cohort is an ongoing prospective study, collecting blood samples from first-trimester-pregnant women since 1975 as part of screening for infectious diseases. A case-control study (212 cases and 369 controls) was nested among Northern Sweden Maternity Cohort members who delivered singleton babies. RIA was used to measure IGF-I and IGF-II levels. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: Breast cancer risk increased with increasing IGF-I (top tertile OR, 1.7; 95% CI, 1.1-2.7). The association was stronger among the primiparous (OR, 2.2; 95% CI, 1.1-4.4) than in the nonprimiparous women (OR, 1.4; 95% CI, 0.7-2.8). Upper-tertile risks seemed to decrease within the <28-, 28 to 33, and >33-year groups of age at sampling, from 2.5 (0.9-7.6) to 2.1 (0.9-5.0) and 1.2 (0.5-2.5), respectively. There was no association of breast cancer with first-trimester-pregnancy IGF-II. CONCLUSIONS: The study offers further evidence that IGF-I is important in breast cancer. Our findings suggest that the adverse effect of IGF-I on the breast may be stronger before the remodeling of the gland induced by a first pregnancy.     

Insulin-like growth factor binding proteins 1 and 3 and breast cancer outcomes

The IGF family of growth factors is believed to play a role in the development and progression of breast cancer. We recently identified an adverse prognostic effect of insulin in breast cancer; we now report prognostic effects of circulating IGFBP's 1 and 3. 512 women with T1-3, N0-1, M0 breast cancer provided fasting blood which was analysed for IGFBP's 1 and 3. Information on body size, diet and traditional prognostic factors and treatment was obtained; women were followed for recurrence and death. IGFBP-1 levels correlated inversely with insulin levels (Spearman r = –0.60, p < 0.0001), reflecting known inhibition of IGFBP-1 gene expression by insulin. Insulin explained 36% of the variance in IGFBP-1 levels. IGFBP-1 levels were also correlated with obesity and diet. Levels of IGFBP-1 significantly predicted distant recurrence and death, hazard ratio (95% CI) for lower versus upper quartile 2.08 (1.20–3.61) and 3.0 (1.45–6.21), respectively. These effects persisted after adjustment for tumor-related variables and treatment but were not independent of insulin levels. High levels of IGFBP-3 predicted distant recurrence (hazard ratio upper v.s. lower quartile 1.8, 95% CI 1.1–3.0) but not death (hazard ratio 1.0, 95% CI 0.5–1.9). The effect on distant recurrence was restricted to postmenopausal women (hazard ratio 3.8, 95% CI 1.6–9.0) and to those with estrogen receptor positive tumors (p = 0.002). Prognostic effects of IGFBP-1 appear related to the known effect of insulin on IGFBP-1 gene expression. The adverse effect of IGFBP-3 on distant recurrence in postmenopausal women with estrogen receptor positive breast cancer should be further investigated.     

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.     

Prospective study of IGF-I,IGF-binding proteins,and breast cancer risk,in northern and southern Sweden

Objective: To examine the possible relationships of breast cancer risk to prediagnostic plasma levels of insulin; insulin-like growth factor-I (IGF-I); and IGF-binding proteins -1, -2, and -3. Methods: Within two prospective cohorts in Umeå and Malmö we measured plasma concentrations of insulin, IGF-I, and IGFBPs for a total of 513 incident breast cancer cases and 987 matched controls. Results: Globally, risk was unassociated with levels of IGF-I, IGFBP-3, or IGF-I adjusted for IGFBP-3. When breaking down the analysis by subgroups of age at blood donation, an increase in risk was observed for increasing levels of IGF-I in women aged 55 or older, in the Umeå cohort only (odds ratios of 1.00, 1.73, 1.76, 1.90; p _trend = 0.05). This effect weakened, however, when the analysis was restricted to subjects who did not use exogenous hormones for the treatment of menopausal symptoms. Levels of IGF-I and IGFBP-3 were not related to risk in younger women, recruited before age 50, contrary to observations from previous studies. In a subcohort where blood samples had been collected after at least four hours of fasting, breast cancer risk showed no clear associations with levels of insulin, IGFBP-1, or IGFBP-2. Conclusions: Our results do not confirm earlier findings of an association of plasma IGF-I levels with breast cancer risk especially in young women, but suggest a possible association with postmenopausal breast cancer risk, possibly among ERT/HRT users only. Our results do not support the hypothesis that elevated plasma insulin levels, and reduced levels of IGFBP-1 and IGFBP-2, are associated with increased breast cancer risk.     

Insulin-like growth factor I,IGF-binding protein 3, and lung cancer risk in a prospective study of men in China

BACKGROUND: Insulin-like growth factor I (IGF-I) stimulates cell proliferation and inhibits apoptosis in the lung and other tissues by interacting with the IGF-I receptor. The major binding protein for IGF-I, insulin-like growth factor-binding protein 3 (IGFBP-3), modulates the effects of IGF-I but also inhibits cell growth and induces apoptosis independent of IGF-I and its receptor. In a prospective study of men in Shanghai, China, we examined the association between serum levels of IGF-I and IGFBP-3 and the subsequent risk of lung cancer. METHODS: From 1986 to 1989, serum was collected from 18,244 men aged 45-64 years living in Shanghai without a history of cancer. We analyzed IGF-I and IGFBP-3 levels in serum from 230 case patients who developed incident lung cancer during follow-up and from 740 control subjects. RESULTS: Among 230 case patients and 659 matched control subjects, increased IGF-I levels were not associated with increased risk of lung cancer. However, for subjects in the highest quartile relative to the lowest quartile of IGFBP-3, the odds ratio (OR) for lung cancer, adjusted for smoking and IGF-I, was 0.50 (95% confidence interval [CI] = 0.25 to 1.02). When the analysis was restricted to ever smokers (184 case patients and 344 matched control subjects), the OR for lung cancer in men in the highest quartile of IGFBP-3 relative to those in the lowest quartile, adjusted for smoking and IGF-I, was 0.41 (95% CI = 0.18 to 0.92). CONCLUSIONS: In this prospective study of Chinese men, higher serum levels of IGF-I did not increase the risk of lung cancer. However, subjects with higher serum levels of IGFBP-3 were at reduced risk of lung cancer. This finding is consistent with experimental data that indicate that IGFBP-3 can inhibit cellular proliferation and induce apoptosis independent of IGF-I and the IGF-I receptor.     

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.     

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.     

Insulin-like growth factor expression in breast cancer epithelium and stroma

Summary The insulin-like growth factors (IGFs) are mitogens for many cancer cell types. In breast cancer cells, IGF-I and IGF-II have both been shown to stimulate cell proliferation. However, IGF-I mRNA has not been found in human breast cancer cell lines, making it unlikely that IGF-I is commonly expressed as an autocrine growth factor for breast cancer cells. Nevertheless, IGF-I mRNA can be detected in breast cancer tissue samples, and in situ hybridization studies have shown that the message originates from the stromal cells adjacent to normal lobules. IGF-II, on the other hand, has been detected in some breast cancer cell lines. In the estrogen receptor positive cell line T47-D, IGF-II mRNA was induced by estradiol. Furthermore, transfection of an IGF-II expression vector into a previously estrogen-dependent cell line resulted in hormone independent growth. Thus, IGF-II can be expressed as an autocrine growth factor in some breast cancers and its expression may, in part, result in hormone independence. Finally, stromal cells obtained from breast tissues showed that IGF-I was commonly expressed in fibroblasts derived from non-malignant biopsy specimens, while IGF-II mRNA was detected in fibroblasts adjacent to malignant tissue. These studies suggest that IGF-II expression may be important in both autocrine and paracrine regulation of breast cancer cell growth.     

Insulin-like growth factor mediated stromal-epithelial interactions in human breast cancer

The prominent desmoplastic or stromal reaction seen in many invasive breast carcinomas lead to early speculation that stromal cells play a role in breast cancer pathogenesis [1]. Experimental evidence now supports this hypothesis and interactions between stromal cells and epithelial cells appear to be important for both normal mammary development and neoplasia. The identification of genes that are selectively expressed in the stroma of malignant breast lesions has recently provided new insights into the molecular basis of stromal-epithelial interactions. Stromally expressed genes include growth factors, proteases and extracellular matrix proteins, all biological activities with potential roles in malignant progression. Investigations discussed here concern the nature of the paracrine signals provided by malignant epithelial cells that activate changes in stromal gene expression, the effect that the stromally derived factors have on the behavior of malignant epithelial cells and the identification of novel factors and receptors in either stroma or epithelia that contribute to their mutual interactions. These questions will be addressed in the context of this laboratory's studies on insulin-like growth factors, as these molecules show marked differences in stromal expression between benign and malignant breast tissue and thus provide a useful paradigm for investigations into the paracrine environment of an evolving breast tumor.     

Insulin-like growth factor II mRNA expression in human breast cancer

Insulin-like growth factor II is a growth factor important in fetal development. Several cancer tissues and cell lines have been reported to express IGF-II and rat IGF-II is mitogenic for breast cancer cell lines. Using Northern analysis and ribonuclease protection assays, IGF-II mRNA was detected in normal fibroblasts and in the established breast cancer cell line, T47D. In this cell line, steady state levels of IGF-II message were increased by treatment with estradiol. 10 nM IGF-II, purified from human serum, was mitogenic for breast cancer cell lines. In vitro, IGF-II may act as an autocrine growth factor for some cell lines. RNA derived from breast cancer, pathologically normal breast tissue, and benign breast disease also contained IGF-II mRNA. When paired samples of normal and cancer tissue were obtained from the breast of the same patient, the level of IGF-II mRNA expression in the normal tissue was at least that found in the cancer. This is consistent with previous observations that show IGF-II is expressed in mesenchyme. These findings suggest that in breast cancer IGF-II is produced by stromal tissue elements and potentially by the malignant epithelial cells. Therefore, IGF-II may function as an autocrine or a paracrine growth factor in different breast tumors.     

Insulin-like growth factors and breast cancer

The insulin-like growth factor (IGF) system performs multiple functions in normal tissue. IGFs are involved in normal mammary gland development, but have also been implicated in the pathogenesis of breast cancer. Epidemiological studies found an association between elevated serum levels of IGF-I and an increased risk for breast cancer. IGF-I is the major mediator of growth hormone (GH) action. On the cellular level, IGF-I has a strong influence on cell proliferation and it is a potent inhibitor of apoptosis. Further, IGFs are also involved in angiogenesis. These characteristics are the basis for their involvement in maintenance and progression of cancer. The functions of IGF-I are mainly mediated through the type-I IGF-receptor (IGF-IR). The availability of free IGF-I for interaction with IGF-IR is modulated by IGF binding proteins (IGFBP 1-6). Based on interactions with other receptors, including estrogen and epidermal growth factor receptors, combined targeted therapies may improve breast cancer treatment.     

Insulin-like growth factor receptor expression and function in human breast cancer

The insulin-like growth factors IGF-I and IGF-II are potent mitogens for several breast tumor cell lines in culture. Additionally, both IGF-I and IGF-II mRNAs are easily detected in the majority of breast tumor specimens examined, while no breast cancer epithelial cell lines we have studied express authentic IGF-I mRNA, and few lines express IGF-II mRNA. Although receptors for insulin, IGF-I, and IGF-II have been described, there is significant cross-reactivity between the various receptors and ligands in the insulin/insulin-like growth factor family, and it is not clear which receptor or receptors are responsible for the biological effects of these growth factors in this system. Using an RNase protection assay, we examined breast tumor specimens and breast cancer epithelial cell lines for expression of mRNA encoding the type I and type II IGF receptors as well as the insulin receptor. Virtually all of the specimens examined expressed mRNA for all three receptors. We then examined estrogen-dependent MCF-7 cells for the mitogenic effects of IGF-I and II in the presence of antibodies to both the type I and type II receptors. alpha IR-3, a monoclonal antibody which blocks the type I receptor, abolished the mitogenic effects of both IGF-I and IGF-II. It did not, however, block the mitogenic effects of insulin. We conclude that type I and type II IGF receptors are ubiquitously expressed in breast cancer, and our experiments with MCF-7 cells suggest the mitogenic effects of both IGF-I and IGF-II are mediated via the type I IGF receptor.     

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,insulin-like growth factor-I (IGF-I), IGF binding proteins,their biologic interactions,and colorectal cancer

Secular changes and worldwide variations in incidence rates of colorectal cancer, along with results from twin and migrant studies, provide compelling evidence that environmental factors influence the risk of this disease. Among the most important of these factors are diet and associated factors, such as physical activity and body size. Recent data suggest that dietary and related factors may influence colorectal cancer risk via their effects on serum insulin concentrations and on the bioavailability of insulin-like growth factor-I (IGF-I). Epidemiologic studies have shown that IGF-I is positively associated with the risk of colorectal cancer, and experimental studies have shown that IGF-I has mitogenic and antiapoptotic actions on colorectal cancer cells. IGF-I bioactivity is regulated in part by its six binding proteins (IGFBP-1 to IGFBP-6); insulin inhibits the production of IGFBP-1 and perhaps IGFBP-2. As a result, chronically elevated fasting and postprandial insulin levels may lead to a decrease in circulating IGFBP-1 and IGFBP-2 concentrations and, consequently, an increase in IGF-I bioavailability. Insulin may also increase the circulating IGF-I/IGFBP-3 ratio by increasing hepatic growth hormone sensitivity. The increased IGF-I bioavailability may, over time, increase the risk of colorectal cancer. This new evidence for biologic interactions among insulin, IGF-I, and IGFBPs in the context of colorectal carcinogenesis provides a potential mechanism through which diet and associated factors may increase the risk of this cancer.     

Insulin-like growth factor receptor (IGF-1R) in breast cancer subtypes

Insulin-like growth factor-1 receptor (IGF-1R) is expressed in normal and malignant breast tissue and has been implicated in cell survival and resistance to cytotoxic therapies. We sought to assess the prognostic impact of IGF-1R expression among patients with early breast cancer and among breast cancer subtypes. Patients with stages I–III breast cancer with archival tumor tissue were included. Paraffin tissue blocks were used to construct a tissue microarray that was stained for ER, PR, Ki-67, HER2, EGFR, and cytokeratins 5/6 to classify the breast subgroups and for expression of IGF-1R, p27, and Bcl2 by immunohistochemistry. Kaplan–Meier plots were created by subtypes. Associations between IGF-1R and prognostic variables were examined in multivariate analysis. Among 2,871 eligible women the prognostic cut point for IGF-1R expression for breast-cancer-specific survival (BCSS) was Allred score <7 versus ≥7. IGF-1R was ≥7 in 52% (LuminalA), 57.5% (LuminalB), 44.8% (LuminalHER2), 9.7% HER2-enriched, and 22.5% (Basal-like), P = 1.3 × 10⁻⁵². IGF-1R+ was associated with age ≥50, lower histopathology grade, ER+, HER2 negativity (−), high p27 and high Bcl2 score. IGF-1R ≥7 was associated with better BCSS among LuminalB patients, hazard ratio = 0.64 (0.49–0.84); P = 1.2 × 10^−3, and worse outcome in the HER2-enriched subtype, hazard ratio = 2.37 (1.21–4.64); P = 0.012. IGF-1R correlates with good prognostic markers among patients with early breast cancer and is differentially expressed with variable prognostic impact among breast cancer subtypes. Results may have relevance to the development of therapeutics targeting IGF-1R.     

Insulin-like growth factor levels in cord blood, birth weight and breast cancer risk

Breast cancer incidence and birth weight are higher among Caucasian than Asian women, and birth size has been positively associated with breast cancer risk. Pregnancy hormone levels, however, have been generally lower in Caucasian than Asian women. We studied components of the insulin-like growth factor (IGF) system in cord blood from 92 singleton babies born in Boston, USA, and 110 born in Shanghai, China, in 1994–1995. Cord blood IGF-1 was significantly higher among Caucasian compared with Chinese babies (P<10⁻⁶). The opposite was noted for IGF-2 (P∼10⁻⁴). IGF-1 was significantly positively associated with birth weight and birth length in Boston, but not Shanghai. In contrast, stronger positive, though statistically non-significant, associations of IGF-2 with birth size were only evident in Shanghai. The associations of birth weight and birth length were positive and significant in taller women (for IGF-1 in Boston P∼0.003 and 0.03, respectively; for IGF-2 in Shanghai P∼0.05 and ∼0.04, respectively), among whom maternal anthropometry does not exercise strong constraints in foetal growth. The documentation of higher cord blood levels of IGF-1, a principal growth hormone that does not cross the placenta, among Caucasian than in Asian newborns is concordant with breast cancer incidence in these populations.