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PubMed2001

Granulosa cell proliferation is impaired in the Igf1 null ovary.

Insulin-like growth factor-I (IGF-I) expression is highly correlated with ovarian follicular growth and granulosa cell proliferation in both pre-pubertal and mature murine ovaries. Igf1 gene deleted mice are infertile, with ovarian follicles arrested at an early stage of development. To elucidate the cause of follicular dysfunction in Igf1 null mice, this study compared granulosa cell proliferation at baseline and in response to exogenous oestradiol (E2) in prepubertal Igf1 null and wild-type (WT) littermate mice. The basal granulosa cell mitotic index was 3.8+/-0.48 in WT and 1.3+/-0.7 in Igf1 null mice (P=0.03). After E2 treatment, WT granulosa mitotic index was 12.7+/-0.0 vs 5.5+/-0.8 for Igf1 null mice (P<0.001). Granulosal BRDU incorporation was also significantly reduced as were cyclin D2 and B1 immunoreactivities in Igf1 null compared with WT mice. The incidence of apoptosis was not increased in Igf1 null follicles, although BAX immunostaining was increased. These data suggest that IGF1 is essential for normal basal and oestrogen-induced granulosa cell proliferation and follicular growth.

Animals↗

PubMed2006

Common genetic variation in IGF1 and prostate cancer risk in the Multiethnic Cohort.

BACKGROUND: Insulin-like growth factor I (IGF-I) appears to play a role in prostate development and carcinogenesis. We investigated whether genetic variation at the IGF1 locus is associated with prostate cancer risk. METHODS: We sequenced IGF1 exons in germline DNA from 95 men with advanced prostate cancer to identify missense variants. IGF1 linkage disequilibrium patterns and common haplotypes were characterized by genotyping 64 single-nucleotide polymorphisms (SNPs) spanning 156 kilobases in 349 control subjects. Associations between IGF1 haplotypes and genotypes were investigated among 2320 patients with prostate cancer and 2290 control subjects from the Multiethnic Cohort. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression to determine the association between prostate cancer and IGF1 haplotypes and genotypes. We used permutation testing to correct for multiple hypothesis testing. All statistical tests were two-sided. RESULTS: No IGF1 missense variants were observed. We identified four blocks of strong linkage disequilibrium and selected a subset of 29 tagging SNPs that could accurately predict both the common IGF1 haplotypes and the remaining SNPs. Haplotype analysis revealed nominally statistically significant associations with prostate cancer risk in each of the four haplotype blocks: haplotype 1B (OR = 1.21, 95% CI = 1.04 to 1.40), haplotype 2C (OR = 1.24, 95% CI = 1.06 to 1.44), haplotype 3C (OR = 1.25, 95% CI = 1.03 to 1.50), and haplotype 4D (OR = 1.19, 95% CI = 1.02 to 1.39). Two SNPs--rs7978742 (Ptrend = .002) and rs7965399 (Ptrend = .002)--were perfectly correlated (correlation coefficient = 1.0) with one another and also associated with prostate cancer risk. These two SNPs were strong proxies for haplotypes 1B, 2C, 3C, and 4D and could account for the haplotype findings. Permutation testing revealed that a similarly strong result would be observed by chance only 5.6% of the time. CONCLUSION: Inherited variation in IGF1 may play a role in the risk of prostate cancer.

Black or African American↗

PubMed2000

Calvariae from fetal mice with a disrupted Igf1 gene have reduced rates of collagen synthesis but maintain responsiveness to glucocorticoids.

The goals of this study were to examine the role of insulin-like growth factor I (IGF-I) on bone formation and to test the hypothesis that the inhibitory effects of glucocorticoids on bone formation are independent of the IGF-I pathway. In serum-free organ cultures of 18-day fetal mouse calvariae derived from Igf1 null mice (Igf1-/-) and their wild-type (Igf1+/+) and heterozygous (Igf1+/-) littermates, we measured the incorporation of [3H]proline into collagenase-digestible protein (CDP) and noncollagen protein (NCP), percent collagen synthesis (PCS), the incorporation of [3H]thymidine into DNA, and messenger RNA (mRNA) levels of osteoblast markers in the presence or absence of dexamethasone. After 24 h of culture, calvariae of all genotypes had similar levels of PCS. However, after 48-96 h of culture, PCS was significantly lower in Igf1-/- calvariae compared with Igf1+/+ calvariae. Treatment of calvariae with 100 nM of dexamethasone for 48-96 h decreased PCS in all genotypes. After 72 h of culture, [3H]thymidine incorporation was similar in all genotypes and 100 nM dexamethasone caused a significant reduction in [3H]thymidine incorporation in all genotypes. Dexamethasone at 100 nM decreased alpha1(I)-collagen (Colla1) mRNA and increased alkaline phosphatase, bone sialoprotein, and osteopontin mRNA in all genotypes after 72 h of culture. Type I IGF receptor mRNA levels were highest in Igf1-/- calvarial cultures. Dexamethasone at 100 nM increased Igf2 and type I IGF receptor mRNA levels in all genotypes. We conclude that one intact allele for Igf1 is sufficient to maintain normal rates of collagen synthesis in fetal mouse calvarial cultures. Moreover, the inhibitory effects of glucocorticoids on collagen synthesis and cell replication are at least partially independent of the IGF-I pathway in this model.

Animals↗

PubMed1994

Site of production of IGF1 in the normal and stimulated mouse thyroid.

Insulin-like growth factor 1 (IGF1) has emerged as an essential factor in the follicular cell growth response in vitro to TSH, although its source within the thyroid in vivo is not clear. We have studied the localisation of IGF1 mRNA by in situ hybridization using digoxigenin labelled oligoprobes in tissue sections of mouse thyroid. Our results show that in the thyroid IGF1 mRNA is predominantly present in follicular cells and C cells rather than the stroma. Follicular cell levels are higher during postnatal thyroid growth and during the growth response to goitrogen administration, but decrease in the mature animal. This decrease in production is limited to the follicular cells, as IGF1 mRNA is still easily demonstrable in C cells and in the parathyroid. Immunocytochemistry for IGF1 peptide shows a weak and variable follicular cell content in both juvenile and mature mice, but a more uniform distribution during growth in response to a goitrogenic stimulus. These studies show that the follicular cells are the main source of IGF1 in the thyroid, and suggest that the role of IGF1 in follicular cell growth is as an autocrine factor.

Aging↗

PubMed2006

Chronic-alcohol exposure alters IGF1 signaling in H9c2 cells via changes in PKC delta.

Previously, we have demonstrated that chronic-alcohol exposure alters insulin-like growth factor 1 (IGF1) signaling in adult rat heart cells. This report examines the effects of alcohol in vitro on the expression of protein kinase C (PKC) alpha, delta, and epsilon using the embryonic heart cell line, H9c2, and how this may be linked to changes in IGF1 signal transduction. Western blot analyses of H9c2 protein preparations demonstrate that there are significant increases in the total protein levels of PKC delta and epsilon after 4 days exposure to alcohol, and similar increases were found after 2 and 6 days exposure. In addition, there was a significant increase in PKC delta and epsilon in the membranal fractions and a decrease in the cytosolic fractions. No change was found in the expression or activity levels for PKC alpha. Chronic-alcohol exposure (100 mM, 4 days) increased the basal tyrosine kinase activity of the IGF1 receptor (IGF1R), and altered its rate of activation. Chronic-alcohol exposure also reduced the rate of Erk1/Erk2 activation by IGF1. Chronic alcohol blocked the proliferative effects of IGF1 on cell growth and reduced cell viability both in the presence and absence of IGF1, and this alcohol-induced reduction in cell viability was blocked using siRNA to inhibit PKC delta. In addition, a reduction in the amount of myosin light chain 2 was found in the alcohol-exposed cells. In conclusion, chronic alcohol alters PKC delta and epsilon expression and activity, and suppresses the IGF1 signaling pathway in embryonic heart cell culture. Blockage of PKC delta expression using siRNA inhibits the suppressive effects of alcohol on cell viability.

Actins↗

PubMed2004

Spontaneous growth hormone secretion and IGF1:IGFBP3 molar ratios in children born small for gestational age (SGA).

OBJECTIVE: To analyze spontaneous nocturnal GH profiles, IGF1 and IGFBP3 serum levels, as well as IGF1:IGFBP3 molar ratios in SGA children without postnatal catch-up growth. METHODS: Short statured prepubertal SGA children (n = 24) were matched retrospectively for sex, age and BMI to short statured children born appropriate for gestational age (AGA), who underwent the same diagnostic program. GH deficiency was excluded in all children by a normal increase of GH in 2 stimulation tests (>8 microg/L). For assessment of spontaneous nocturnal GH secretion, GH serum levels were measured every 20 min for 10 h. Pulsatility was analyzed with Pulsar. RESULTS: None of the Pulsar derived descriptive parameters showed a significant difference between SGA and AGA children. Overall, median IGF1 levels were approximately one SDS below zero SDS (p < 0.001), whereas IGFBP3 levels were normal in both groups. Thus, the IGF1:IGFBP3 molar ratios were significantly lower from zero (p < 0.01) in SGA as well as in AGA children. However, IGF1- and IGFBP3-SDS levels related either to chronological or to bone age did not differ significantly between SGA and AGA children. CONCLUSIONS: Building matched pairs of short statured children born either SGA or AGA for sex, age and BMI we did not find any significant differences in spontaneous nocturnal GH secretion, IGF1, IGFBP3, and IGF1:IGFBP3 molar ratios.

Body Mass Index↗

PubMed1999

Igf1 promotes longitudinal bone growth by insulin-like actions augmenting chondrocyte hypertrophy.

Longitudinal bone growth, and hence stature, are functions of growth plate chondrocyte proliferation and hypertrophy. Insulin-like growth factor 1 (Igf1) is reputed to augment longitudinal bone growth by stimulating growth plate chondrocyte proliferation. In this study, however, we demonstrate that chondrocyte numbers and proliferation are normal in Igf1 null mice despite a 35% reduction in the rate of long bone growth. Igf1 null hypertrophic chondrocytes differentiate normally in terms of expressing specialized proteins such as collagen X and alkaline phosphatase, but are smaller than wild-type at all levels of the hypertrophic zone. The terminal hypertrophic chondrocytes, which form the scaffold on which long bone growth extends, are reduced in linear dimension by 30% in Igf1 null mice, accounting for most of their decreased longitudinal growth. The expression of the insulin-sensitive glucose transporter, GLUT4, is significantly decreased and the insulin-regulated enzyme glycogen synthase kinase 3beta (GSK3) is hypo-phosphorylated in Igf1 null chondrocytes. Glycogen levels were significantly decreased and ribosomal RNA levels were reduced by almost 75% in Igf1 null chondrocytes. These data suggest that Igf1 promotes longitudinal bone growth by 'insulin-like' anabolic actions which augment chondrocyte hypertrophy.

Animals↗

PubMed1992

Insulin and IGF1 receptors in a model renal epithelium: receptor localization and characterization.

Insulin and IGF1 stimulate transepithelial Na+ transport in the urinary bladder of the toad Bufo marinus, a model renal epithelium. The signal transduction mechanisms for the natriferic action are unknown. Ultrastructural techniques were used to localize both receptors and ligands in the epithelium. Electron microscopy using gold-labelled anti-insulin or anti-IGF1 receptor antibodies demonstrated the majority of the insulin receptors were associated with the basolateral membrane while IGF1 receptors were found on basolateral and apical membranes. Both insulin and IGF1 receptors were found in endosomes and on the membranes surrounding subapical granules. In intact tissues incubated with iodinated IGF1 or insulin, both ligands were associated with the basolateral membrane. IGF1 was internalized to a greater extent than insulin and only IGF1 accumulated in cell nuclei.

Animals↗

PubMed2006

Expression analysis of peptide growth factors VEGF, FGF2, TGFB1, EGF and IGF1 in prostate cancer and benign prostatic hyperplasia.

Peptide growth factors play an important role in several intracellular processes, such as cellular growth and differentiation, angiogenesis and apoptosis, as well as in carcinogenesis, since they contribute significantly to the malignant transformation. The prostate gland is abundant in growth factors. The two most known prostatic diseases, prostate cancer (PCa) and benign prostatic hyperplasia (BPH), are among the most common diseases that affect elderly men. This study was conducted using a quantitative real-time RT-PCR method in order to determine mRNA expression levels of peptide growth factors VEGF, FGF2, TGFB1, EGF, and IGF1 in tissue specimens from 42 patients with PCa, 42 with BPH, and 10 normal prostate samples obtained post-mortem from young individuals, in order to examine their association with prostatic hyperplasia and neoplasia. Our results show that in PCa, growth factors VEGF, EGF and FGF2 are overexpressed, while TGFB1 and IGF1 have reduced mRNA levels. In BPH, transcript levels of FGF2 and EGF are normal, while VEGF, TGFB1 and IGF1 exhibit downregulation. Further statistical analysis revealed that PCa patients with high levels of PSA blood levels have decreased FGF2 expression (p=0.016). Additionally, cancer patients with low Gleason score (<7) have increased EGF (p=0.035) and IGF1 (p=0.031) mRNA levels. IGF1 levels are also elevated in tumors with TNM stages T1-T2 (p=0.030). In BPH, older patients have reduced EGF expression (p=0.018), while IGF1 is overexpressed in younger patients (p=0.041). Additionally, the co-expression pattern of the five studied growth factors differs significantly among normal, benign and malignant prostate. These results implicate VEGF, FGF2, TGFB1, EGF and IGF1 in the development of both PCa and BPH, rendering them potential targets for disease detection, monitoring and therapy.

Adult↗

PubMed1993

Impairment of myocyte contractility following coronary artery narrowing is associated with activation of the myocyte IGF1 autocrine system, enhanced expression of late growth related genes, DNA synthesis, and myocyte nuclear mitotic division in rats.

To determine whether the alterations in ventricular loading and myocyte cellular contractile performance produced by short-term coronary artery constriction were associated with the activation of genes implicated in myocyte DNA synthesis including changes in the expression of insulin-like growth factor-1 (IGF1) and insulin-like growth factor-1 receptors (IGF1-R), nonocclusive coronary artery narrowing (CAN) was induced in rats. Animals were examined 2 and 7 days after coronary constriction. Following the in vivo documentation of severe impairment of ventricular performance, estimations of single-cell mechanics in vitro showed that peak shortening was decreased in left and right myocytes of coronary stenosed rats. Moreover, time to peak shortening was prolonged whereas velocity of shortening was decreased. These defects in myocyte contractility were accompanied by increases in cell length and width, indicative of myocyte enlargement biventricularly. In addition, CAN led to an enhanced expression of proliferating cell nuclear antigen (PCNA) and histone-H3 genes in myocytes at 2 and 7 days after surgery. PCNA protein was also detected in these stressed cells. These molecular responses were associated with increases in mRNA for IGF1 and IGF1-R in combination with enhanced DNA synthesis and appearance of myocyte nuclear mitotic division. In conclusion, cardiac myocytes may respond to the elevation in wall and myocyte stress by activating an IGF1-IGF1-R autocrine system which may modulate the induction of late growth related genes which are essential for DNA replication and myocyte cellular hyperplasia.

Animals↗

PubMed1990

Polymorphism and mapping of the IGF1 gene, and absence of association with stature among African Pygmies.

Probes detecting restriction fragment length polymorphisms (RFLPs) in the insulinlike growth factor (IGF1) gene were isolated and allele frequencies in different human populations determined. No difference was detected between the distribution of IGF1 alleles in Pygmies versus non-Pygmy black Africans, despite the proposal that a defect in the IGF1 gene might be responsible for Pygmy short stature. This was supported by the absence of a correlation of IGF1 genotype with height in the C.A.R. Pygmies. Polymerase chain reaction (PCR) and direct sequencing failed to demonstrate an alteration in the region upstream the IGF1 start site in Pygmies. Linkage analysis demonstrated that IGF1 is tightly linked to the phenylalanine hydroxylase gene on chromosome 12q22-24.1.

Africa↗

PubMed2002

beta-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass.

Regulation of glucose homeostasis by insulin depends on the maintenance of normal beta-cell mass and function. Insulin-like growth factor 1 (Igf1) has been implicated in islet development and differentiated function, but the factors controlling this process are poorly understood. Pancreatic islets produce Igf1 and Igf2, which bind to specific receptors on beta-cells. Igf1 has been shown to influence beta-cell apoptosis, and both Igf1 and Igf2 increase islet growth; Igf2 does so in a manner additive with fibroblast growth factor 2 (ref. 10). When mice deficient for the Igf1 receptor (Igf1r(+/-)) are bred with mice lacking insulin receptor substrate 2 (Irs2(-/-)), the resulting compound knockout mice show a reduction in mass of beta-cells similar to that observed in pancreas of Igf1r(-/-) mice (ref. 11), suggesting a role for Igf1r in growth of beta-cells. It is possible, however, that the effects in these mice occur secondary to changes in vascular endothelium or in the pancreatic ductal cells, or because of a decrease in the effects of other hormones implicated in islet growth. To directly define the role of Igf1, we have created a mouse with a beta-cell-specific knockout of Igf1r (betaIgf1r(-/-)). These mice show normal growth and development of beta-cells, but have reduced expression of Slc2a2 (also known as Glut2) and Gck (encoding glucokinase) in beta-cells, which results in defective glucose-stimulated insulin secretion and impaired glucose tolerance. Thus, Igf1r is not crucial for islet beta-cell development, but participates in control of differentiated function.

Animals↗

PubMed2005

Insulin-like growth factor-1 (IGF1) genotype predicts breast volume after pregnancy and hormonal contraception and is associated with circulating IGF-1 levels: implications for risk of early-onset breast cancer in young women from hereditary breast cancer families.

BRCA1/2 mutations predispose to early-onset breast cancer, especially after oral contraceptive (OC) use and pregnancy. However, the majority of breast cancers might be due to more prevalent low-penetrance genes, which may also modify the risk in BRCA mutation carriers. The absence of the IGF1 19-repeat allele has been associated with high insulin-like growth factor-1 (IGF-1) levels during OC use. High IGF-1 levels are linked to early-onset breast cancer and larger breast volumes in the general population. The goal of this study was to elucidate the relationships between IGF1 genotype, early-onset breast cancer, breast volume, circulating IGF-1 levels and OC use in a prospective cohort of 258 healthy women < or =40 years old from high-risk breast cancer families. All women completed a questionnaire including information on reproductive factors and OC use. We measured the height, weight, breast volumes and plasma IGF-1 levels. IGF-1 levels were similar among parous and nulliparous women not using OCs. In all, 13% had no IGF1 19-repeat allele. There was an interaction between IGF1 genotype and OC use on IGF-1 levels (P=0.026) in nulliparous women and another interaction between IGF1 genotype and parity on breast volume (P=0.01). Absence of the 19-repeat allele was associated with high IGF-1 levels in nulliparous OC users and with larger breast volumes in parous women and OC users. Incident breast cancers were also more common in women without the 19-repeat allele (log rank P=0.002). Our results suggest that lack of the IGF1 19-repeat allele modifies IGF-1 levels, breast volume and possibly early-onset breast cancer risk after hormone exposure in young high-risk women.

Age of Onset↗

PubMedDate not supplied

Local application of IGF1 on dental pulp mechanically exposed; in vivo study on rabbit.

IGF1 (Insulin Growth Factor, 1) was intentionally applied onto pulp tissues, aiming to provoque a dentine regeneration process through the stimulation of the dentinoblasts' potententials. 72 cavities were hence performed on rabbit molars, intentionally exposing the dental pulp. Different concentrations of IGF1 were then applied; The histo and anatomo-pathological observations showed persistent vitality of the pulp without any sign of necrosis, even 6 weeks after the IGF1 application. Dentinoblasts layers (as an indication of the regeneration activity) were counted, according to a pre-established protocol, at days 7, 14, 22, 28 and 42. The type of the applied IGF1, was carefully selected to be "Binding Protein Resistant" (IGF-BPR), so to avoid any inhibition of the IGF1 action by the endogenous binding proteins (Hochscheid and coll). The results were conclusive in indicating the IGF1 as an efficient dental pulp capping product.

Animals↗

PubMed2004

Effects of early nutrition intervention on IGF1, IGFBP3, intestinal development, and catch-up growth of intrauterine growth retardation rats.

OBJECTIVE: To investigate the effects of early nutritional intervention on the serum insulin-like growth factor-1 (IGF1), insulin-like growth factor binding protein 3 (IGFBP3), intestinal development, and catch-up growth of intrauterine growth retardation (IUGR) rats by giving the IUGR new born rats different protein level diet. METHODS: IUGR rat model was built by starvation of pregnant female rats. Twenty-four IUGR pups and 8 normal pups were divided randomly into 4 groups: normal control group (C group); IUGR control group (S group), IUGR low-protein diet group (SL group), and IUGR high-protein diet group (SH group). Detected the serum IGF1, IGFBP3, body weight, body length, intestinal weight length, intestinal villi height (VH), crypt depth (CD), villi absorbing area (VSA), mucous thickness (MT), and disaccharidase at the 4th week. RESULTS: (1) The SH group showed the fastest catch-up growth, serum IGF1, IGFBP3, VH, and VSA were significantly higher than those of normal control group and IUGR control group. The intestinal weight and length, and the activities of lactase and saccharase of the SH group also reached the normal control group level. (2) The SL group kept on small size, the serum IGF1, IGFBP3, and most of intestinal histological indexes were all significantly lower than other groups. (3) IGF1, IGFBP3 were positively correlated to intestinal VH, VSA, saccharase, body weight and length. CONCLUSIONS: The serum IGF1 was a sensitive index to the catch-up growth. The early nutritional intervention of high-protein diet after birth is helpful for the catch-up growth of IUGR through promoting the intestinal development and the absorption of nutrition.

Animals↗

PubMed1994

Signaling by insulin-like growth factors in paralyzed skeletal muscle: rapid induction of IGF1 expression in muscle fibers and prevention of interstitial cell proliferation by IGF-BP5 and IGF-BP4.

In the absence of muscle activity, muscle fibers, muscle interstitial cells, and intramuscular nerves display characteristic reactions presumably aimed at restoring a functioning neuromuscular system and avoiding degenerative events. In partially denervated muscle these include proliferation of interstitial cells, followed by nerve sprouting. The same reactions can be induced in intact muscle by elevation of intramuscular insulin-like growth factor (IGF) levels. To determine whether IGFs may participate in the initiation of restorative reactions in inactivated muscle we analyzed the expression of IGF1 and IGF2 mRNA in botulinum toxin-paralyzed and in denervated rat skeletal muscle, and interfered with the activity of IGFs by locally applying the IGF-binding proteins IGF-BP5 and IGF-BP4. To obtain a resolution of the in situ hybridization signals at the cellular level, a nonradioactive method based on digoxigenin-labeled probes was applied. We found that muscle fiber IGF1 mRNA increased rapidly and transiently in inactivated muscle. The time course of this response was similar to that reported for ACh receptor subunits and myogenins. A similar behavior was observed for the corresponding IGF1 protein. The IGF1 response coincided with the transient muscle interstitial cell proliferation reaction. Local application of recombinant IGF-BP5 or IGF-BP4, which are endogenous and specific extracellular ligands of IGFs, prevented the stimulation of interstitial cell proliferation in paralyzed muscle. Our data demonstrate the elevated production of the growth factor IGF1 among early reactions in electrically inactive skeletal muscle fibers and indicate that muscle IGFs are required for the induction of intramuscular interstitial cell proliferation. These findings support the hypothesis that in the neuromuscular system IGF1 plays an important role in initiating cellular reactions in the vicinity of inactive muscle fibers.

Animals↗

PubMed2000

IGF1 activates PKC alpha-dependent protein synthesis in adult rat cardiomyocytes.

Acute exposure to interleukin 1 beta (IL1beta) or insulin-like growth factor 1 (IGF1) promoted the translocation of PKC alpha from the cytosol to the membrane of adult rat cardiomyocytes. Western analysis demonstrated that membranal localization of PKC alpha was increased from 23% in the control to 49% after exposure to IGF1, and it was increased to 42% after exposure to IL1beta. Activation of Erk1/Erk2 by IGF1 and IL1beta was studied using a phosphorylation-specific antibody. IGF1-induced activation of p44/p42 MAP kinase was blocked by preincubation with the PKC inhibitors, bisindolylmaleimide and Gö6976, as well as the tyrosine kinase inhibitor, genistein. IGF1 increased the rate of protein synthesis, indicated by the increase in L-[(14)C(U)] phenylalanine incorporation over time, and this effect was inhibited by Gö6976.

Animals↗

PubMed2006

Genetic variation in IGF1, IGFBP3, IRS1, IRS2 and risk of breast cancer in women living in Southwestern United States.

BACKGROUND: An insulin-related pathway to breast cancer has been hypothesized. METHODS: We examine the 19 CA repeat of the IGF1 gene, the -202 C > A IGFBP3, the G972R IRS, and the G1057D IRS2 polymorphisms among 1,175 non-Hispanic white (NHW) and 576 Hispanic newly diagnosed breast cancer cases and 1,330 NHW and 727 Hispanic controls living in Arizona, Colorado, New Mexico, and Utah. RESULTS: Among post-menopausal women not recently exposed to hormones, not having the 19 CA repeat of IGF1 gene was associated with breast cancer among NHW women [odds ratio (OR) 2.14, 95% confidence interval (CI) 1.21-3.79] and having an R allele of G972R IRS1 increased breast cancer risk among Hispanic women (OR 2.70, 95% CI 1.13-6.46). Among post-menopausal Hispanic women recently exposed to hormones the A allele of the -202 C > A IGFBP3 polymorphism increased risk of breast cancer (OR 1.57, 95% CI 1.06-2.33). The IGF1 19 CA repeat polymorphism interacted with hormone replacement therapy (HRT) among NHW post-menopausal women; women who had the 19/19 IGF1 genotype were at reduced risk of breast cancer (OR 0.64, 95% CI 0.47-0.88) if they did not use HRT. We also observed interaction between body mass index and IGF1 19 CA repeat (p=0.06) and between weight gain and the -202 C > A IGFBP3 polymorphism (p=0.05) in NHW post-menopausal women not recently exposed to hormones. CONCLUSIONS: Our data suggest that associations between insulin-related genes and breast cancer risk among women living in the Southwestern United States may be dependent on estrogen exposure and may differ by ethnicity.

Adolescent↗