Clinical significance of serum insulin-like growth factor-1 (IGF-1) and insulinlike growth factor binding protein-3 (IGFBP-3) in patients with epithelial ovarian cancer

Insulin-like growth factor-1 (IGF-1) and its primary binding protein IGFBP-3 play an important role in cellular proliferation, differentiation, and apoptosis in many tumors, including ovarian cancer. The objective of this study was to determine the clinical significance of the serum levels of IGF-1 and IGFBP-3 in epithelial ovarian cancer (EOC) patients. A total of 50 patients with a pathologically confirmed diagnosis of EOC were enrolled into this study. Serum IGF-1 and IGFBP-3 levels were determined by the solid-phase sandwich ELISA method. Twenty age- and sex-matched healthy controls were included in the analysis. Median age of patients was 56.5 years old (range 22 to 83 years). Majority of the patients had advanced disease (FIGO stage III–IV; 90 %). No significant difference was observed in baseline serum IGF-1 and IGFBP-3 levels between EOC patients and healthy controls (p?=?0.99 and p?=?0.80, respectively). The young patients had higher serum IGF-1 and IGFBP-3 concentrations (p?=?0.04 and p?=?0.02, respectively). Patients with normal CA-125 levels had higher serum IGFBP-3 concentrations compared with those with higher CA-125 levels (p?=?0.008). However, no other clinical variables including histology, tumor grade, stage of disease, and response to chemotherapy were found to be correlated with serum IGF assays (p?>?0.05). A trend to significant relationship was found between the serum levels of IGF-1 and IGFBP-3 (r _s?=?0.212, p?=?0.07). The patients with elevated serum IGF-1 levels had favorable progression-free and overall survivals than those with lower levels (p?=?0.04 and p?=?0.03, respectively). However, serum IGFBP-3 concentrations were found to have no prognostic role for both survivals (p?=?0.12 and p?=?0.26, respectively). In conclusion, elevated serum level of IGF-1 is associated with favorable progression-free and overall survivals in EOC patients.     

乳腺癌患者血清瘦素及胰岛素样生长因子-1检测的临床意义

目的:探讨乳腺癌患者血清瘦素(leptinLEP)、胰岛素样生长因子-1(insulin-likegrowthfactor-1,IGF-1)检测的临床意义。方法:采用酶标记免疫吸附法测定女性乳腺癌、乳腺良性病变患者血清中LEP、IGF-1的浓度,并与其他临床资料进行对比分析。结果:LEP、IGF-1浓度在乳腺癌组与乳腺良性病变组、乳腺癌腋窝淋巴结转移组阳性与阴性组比较差异有统计学意义,P<0·05。乳腺癌组与乳腺良性疾病组LEP、IGF-1浓度与月经状态有关,P<0·05。结论:血清LEP、IGF-1水平与女性乳腺癌患者的预后及月经状态有关。     

Clinical significance of serum circulating insulin-like growth factor-1 (IGF-1) mRNA in hepatocellular carcinoma

The principal aim of our study was to investigate the usefulness of serum protein and circulating mRNA of insulin-like growth factor-1 (IGF-1) as a diagnostic and prognostic tool in hepatocellular carcinoma (HCC). Fifty-four HCC patients and age- and sex-matched 20 healthy controls were enrolled into this study. Pretreatment serum IGF-1 and IGF-1 mRNA were determined by the solid-phase sandwich ELISA and quantitative RT-PCR method, respectively. The median age at diagnosis was 60 years, range 36–77 years; where majority of group were male (n?=?48, 88.8 %). All patients had cirrhotic history. Forty-six percent (n?=?25) of patients had Child-Pugh score A, 30 % (n?=?16) had score B or C. All of the patients were treated with local therapies and none of them received sorafenib. The baseline serum IGF-1 mRNA levels were significantly higher in HCC patients than in the control group (p?=?0.04), whereas no significant difference was observed for IGF-1 protein levels between the two group (p?=?0.18). Patients with history of HBV infection, who were not treated, and who received multiple palliative treatment for HCC had higher serum IGF-1 mRNA levels (p?=?0.03, 0.03, and 0.05, respectively). Poor performance status (p?<?0.001), viral etiology of cirrhosis (p?=?0.03), larger tumor size (p?=?0.01), lower serum hemoglobin levels (p?=?0.03), and not be treated for HCC (p?=?0.001) related to worse survival. However, neither serum IGF-1 nor serum IGF-1 mRNA had significantly adverse effect on survival (p?=?0.53 and 0.42, respectively).     

Insulin-like growth factor binding protein-1 (IGFBP-1) inhibits breast cancer cell motility

The breast cancer malignant phenotype is regulated by steroid hormones and peptide growth factors. We have shown previously that insulin-like growth factor-I (IGF-I) stimulates cell motility in a metastatic cell line, MDA-231BO. In this study, we show that neutralization of IGF action by a type I IGF receptor (IGFR1) blocking antibody or neutralization of IGF-I by IGFBP-1 reduced cell motility. However, in addition to inhibiting IGF effects, IGFBP-1 also diminished basal motility. Because IGFBP-1 contains a RGD motif important in binding of fibronectin to its alpha 5 beta 1 integrin receptor, we examined the effect of inhibiting integrin function on cell motility. As expected, disruption of fibronectin-integrin interactions interrupted basal motility in MDA-231BO cells. In addition, disruption of integrin function by an alpha 5 beta 1 blocking peptide also inhibited IGF stimulation of cell motility. To determine whether integrin function could interfere with IGF signaling, we used an alpha 5 beta 1 blocking peptide to show that in MDA-231BO cells integrin occupancy appeared necessary for phosphorylation of insulin receptor substrate-2 but not for IGFR1 activation. We conclude that IGFR1 and integrin action are linked in these breast cancer cells as disruption of integrin binding to its receptor influences IGF signaling pathways. Moreover, IGFBP-1 could have dual effects on cancer cell motility by disrupting both receptor systems.     

Plasma levels of insulin-like growth factor-1 and insulin-like growth factor binding protein-3 in women with cervical neoplasia

Objective

The goal of this study was to investigate the relationship between plasma levels of insulin-like growth factors-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) and the risk for cervical intraepithelial neoplasia (CIN) and cervical cancer.

Methods

Plasma levels of IGF-1 and IGFBP-3 of 44 cervical cancer patients, 82 CIN patients and 40 neoplasm-free patients were investigated. Then the associations of the plasma levels of IGF-1 and IGFBP-3 with cervical neoplasm or its clinicopathologic parameters were analyzed.

Results

The mean IGF-1 concentrations were significantly different among the control, CIN, and cervical cancer groups; the levels were higher in the CIN group compared to the controls. According to the quartile category, the plasma IGF-1 level was significantly higher (p=0.0015) in the CIN group than in the controls. The IGFBP-3 level showed no association between the controls and CIN groups (p=0.842). Although the mean IGF-1/IGFBP-3 molar ratio had borderline significance (p=0.08) among the study population, the quartile comparison showed a significantly higher IGF-1/IGFBP-3 molar ratio in the CIN group compared to the control group (p=0.041).

Conclusion

Plasma levels of IGF-1 and the IGF-1/IGFBP-3 molar ratio might be useful for the development early detection of cervical lesions and used as an adjuvant diagnostic tool for cervical neoplasia after more larger scale research.     

Insulin-like growth factor binding protein-3 (IGFBP-3) potentiates paclitaxel-induced apoptosis in human breast cancer cells

Variability in response to chemotherapy is poorly understood. Paclitaxel-induced apoptosis was assessed in human Hs578T breast cancer cells, using the MTT assay, cell counting, morphological features and flow cytometry. Pre-dosing cells with non-glycosylated insulin-like growth factor binding protein-3 (ngIGFBP-3) had no effect on the cells per se but accentuated paclitaxel-induced apoptosis. The apoptotic pathway was further examined by measuring caspase-3 activity in cell lysates at time points over 48 hr after dosing with paclitaxel. Activity increased significantly, and Western immunoblots for caspase-3 in conditioned media showed that the inactive precursor decreased after incubation with paclitaxel. Endogenous production of IGFBP-3 by the cells after incubation with paclitaxel was evaluated using Western ligand blotting, specific IGFBP-3 immunoblotting and radioimmunoassay. Paclitaxel increased endogenous IGFBP-3, which was further increased if the cells had been pre-dosed with ngIGFBP-3. These findings suggest that IGFBP-3 may be an important modulator of paclitaxel-induced apoptosis.     

Variation in plasma insulin-like growth factor-1 and insulin-like growth factor binding protein-3: genetic factors.

Insulin-like growth factors (IGFs) play key roles in cell proliferation and apoptosis. Whereas relatively stable within individuals, IGFs vary substantially between individuals, and a large component of this variation may be determined by genetic factors. Several polymorphisms in IGF genes have been identified, although their functional significance is not clear. We evaluated the association of polymorphisms in IGF-1 and IGFBP-3 and circulating levels of IGF-1 and IGFBP-3 in 323 population-based control subjects enrolled in a case-control study of colorectal cancer from September 1999 through February 2002. Total IGF-1 and IGFBP-3 levels were measured using ELISA assays, and all subjects were genotyped for a microsatellite polymorphism in IGF-1 and a single nucleotide polymorphism in IGFBP-3. Multiple linear regression was used to assess the association of genotype with circulating IGFs. IGF-1 levels were unrelated to either polymorphism. IGFBP-3 was significantly associated with IGFBP-3 genotype, with IGFBP-3 levels increasing from CC (1,895 ng/mL) --> GC (2,029 ng/mL) --> GG (2,182 ng/mL), (p-trend < 0.001). Having an IGF-1 genotype other than homozygous for the 19-repeat allele was associated with higher IGFBP-3 levels (1,945 versus 2,052 ng/mL). Furthermore, both IGF-1 and IGFBP-3 genotypes modified the relationship between postmenopausal hormone use and IGFs. This analysis provides evidence that common variation in IGF genes may contribute to the variation in circulating levels observed between individuals.     

应用IGF-1基因缺失小鼠研究IGF-1与乳腺肿瘤血管生成的关系

背景与目的:胰岛素样生长因子家族(insulin-like growth factors,IGFs)在肿瘤发生发展中所起的作用日益受到重视,但其作用机制尚不清楚.本实验通过在肝特异性胰岛素样生长因子1(insulin-like growth factor 1,IGF-1)基因缺失(LID)小鼠体内建立稳定的原发性乳腺癌模型,探讨血清中IGF-1水平与乳腺肿瘤血管生成可能存在的关系.方法:使用肝特异性IGF-1基因缺失小鼠及对照鼠,用化学致癌剂7,12-二甲基苯蒽[7,12-dimethybenz(a)anthracene,DMBA]诱导原发性乳腺肿瘤,使用人参皂甙Rg3进行干预治疗.比较各组肿瘤发生情况并通过免疫组化方法检测血管内皮生长因子(vascular endothelial growth factor,VEGF)的表达及微血管密度(microvessel density,MVD).结果:未管饲Rg3的对照鼠、未管饲Rg3的LID鼠、管饲Rg3的对照鼠及管饲Rg3的LID鼠的乳腺癌发病率依次为66.67%、33.33%、36.00%及12.00%.肿瘤平均直径四组依次为(0.79±0.20)cm、(0.37±0.08)cm、(0.32±0.08)cm及(0.15±0.05)cm.VEGF表达检测:未管饲Rg3的对照鼠平均光密度为0.34±0.10,阳性百分率(positive rate,PR)为0.04±0.02,均为各组中最高(P＜0.05);管饲Rg3的LID鼠平均光密度0.13±0.03,阳性百分率0.01±0.00,均为各组中最低(P＜0.05).以上四组MVD依次为31.9±5.3、26.8±4.9、20.1±4.9、14.4±4.9(P＜0.05).结论:IGF-1与乳腺肿瘤的发生发展相关,降低血清IGF-1可抑制肿瘤血管生成而对乳腺肿瘤有抑制作用,应用血管生长抑制剂人参皂甙Rg3可增强这一效应.     

Elevated insulin-like growth factor-1 and insulin-like growth factor binding protein-2 in malignant pleural effusion

Insulin-like growth factor-1 (IGF-1) and its binding proteins (IGFBPs) are produced by many tissues and are present in serum and other biological fluids. Alterations in sera of IGF-1 and 2 and IGFBPs were demonstrated in patients with malignancy, infection and other diseases causing pleural effusion. In this study the IGF-1 and IGFBP-2 content and the specific electrophoretic patterns of IGFBPs in samples of sera and pleural effusions of 25 patients with malignancy, infection and congestive heart failure were investigated. IGF-1 levels in exudative effusions of malignant solid tumors were significantly higher [(mean +/- SD), 20.9+/-7.5 nmol/L, n = 9] than in lymphoma (11.0+/-5.2 nmol/L, n = 5; p < 0.05), infection (11.4+/-6.5 nmol/L, n = 6; p < 0.05) and transudative effusion of congestive heart failure (4.3+/-3.3 nmol/L, n = 5; p < 0.02). IGFBP-2 was markedly increased in effusions of malignant solid tumors (2.14+/-0.82 mg/L, n = 9) compared with exudates of lymphoma, infection and transudates (1.10+/-0.70, 1.22+/-0.32 and 0.93+/-0.52 nmol/L, respectively, p < 0.05). Moreover, in effusion of solid tumors, IGFBP-2 levels were higher than those in corresponding sera, which suggests local production of this binding protein. The demonstration of IGFBP-2 in solid tumor cells by immunohistochemistry further supports this possibility. This work demonstrates the existence of the IGF-1/IGFBP system in pleural fluids from different etiologies and implies possible use of IGF-1 and IGFBP-2 as a potential marker of malignant effusions.     

Elevated serum insulin-like growth factor (IGF)-II and IGF binding protein-2 in patients with colorectal cancer

This study explored the relationships of serum insulin-like growth factors, IGF-I and IGF-II, and their binding proteins (IGFBP)-2 and IGFBP-3, with key clinicopathological parameters in 92 patients with colorectal cancer (cases). Comparisons were made with 57 individuals who had a normal colonoscopy (controls). Serial changes were examined in 27 cases. As IGF-related peptides are age- and sex-dependent, absolute concentrations were converted to standard deviation scores (SDS). Mean IGF-II SDS were elevated in Dukes A (n = 12, P< 0.001) and Dukes B (n = 25, P< 0.001) cases compared with controls, but not in advanced disease. Compared with controls, mean IGFBP-2 SDS were significantly elevated in patients with Dukes B (P< 0.001), Dukes C (n = 13, P< 0.001) and advanced disease (n = 42, P< 0.0001), with a significant trend from early to advanced disease (one-way ANOVA, P< 0.001). Furthermore, IGFBP-2 SDS were positively related to tumour size (P = 0.01) and fell significantly in patients following curative resection (P = 0.04), suggesting that circulating levels reflect tumour load. We tested the potential tumour marker characteristics of IGFBP-2 SDS against three endpoints: metastasis alone; local pelvic recurrence alone; and metastasis and recurrence combined. The sensitivities for IGFBP-2 alone (>/= + 2SD) were modest at 55%, 46%, and 52%, but in combination with CEA, increased substantially to 90%, 77% and 86%, respectively. We conclude that the serum IGF-II and IGFBP-2 profiles may provide insights into underlying biological mechanisms, and that serum IGFBP-2 may have an adjunct role in cancer surveillance in patients with colorectal cancer.     

The prognostic significance of pretreatment plasma levels of insulin-like growth factor (IGF)-1, IGF-2, and IGF binding protein-3 in patients with advanced non-small cell lung cancer

PURPOSE: Insulin-like growth factor (IGF) system is related to cell proliferation and tumor growth. We tested whether pretreatment plasma levels of IGF-1, IGF-2, and IGF binding protein (IGFBP)-3 would predict the prognosis in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Plasma levels of IGF-1, IGF-2, and IGFBP-3 were measured using enzyme-linked immunoassays from 77 patients with advanced NSCLC enrolled in a phase II study of irinotecan plus cisplatin chemotherapy. RESULTS: IGF-2 and IGFBP-3 levels were elevated in female patients, non-squamous cell carcinoma, and never smokers. In a univariate Cox proportional hazards model, higher levels of IGF-1, IGF-2, and IGFBP-3 were predictive of longer progression-free (P=0.001, 0.006, and 0.007, respectively) and overall survival (P=0.025, <0.0001, and 0.001, respectively). Multivariate analysis revealed that IGF-1 and IGFBP-3 are independent factors for progression-free survival (P<0.0001 and P=0.001, respectively). In addition, IGF-1, IGF-2, and IGFBP-3 are independently predictive for overall survival (P=0.004, 0.001, and 0.043, respectively). CONCLUSIONS: High plasma levels of IGF-1, IGF-2, and IGFBP-3 were associated with good prognosis in patients with advanced NSCLC. Further validation of these results is needed to determine the prognostic significance of IGF system in advanced NSCLC.     

Plasma insulin-like growth factor binding protein-3 proteolysis is increased in primary breast cancer.

Fasting blood samples were obtained before definitive surgery or biopsy in 128 patients referred to the department of surgery with suspected or manifest breast cancer. Insulin-like growth factor (IGF)-I, IGF-II and free IGF-I were measured by radioimmunoassay/immunoradiometric assay, while IGFBP-3 proteolysis was evaluated by Western immunoblot. 12 patients had ductal carcinoma in situ benign conditions, while staging revealed metastatic disease in 15 of 16 patients with invasive cancers. IGFBP-3 proteolysis above the normal range was recorded in 19 patients with invasive cancers, but in none of the patients suffering from DCIS/benign conditions. Increased IGFBP-3 proteolysis was most frequently recorded in patients harbouring large tumours and metastatic disease (Stage I: 0/19, 0%; Stage II: 3/45, 7%, Stage III: 9/37, 24%, and Stage IV: 7/15, 47%). IGFBP-3 proteolysis was significantly higher in Stage III (P =0.01) and IV (P< 0.001) patients compared to the other stage groups (P = 0.001). IGF-I and IGF-II correlated negatively to IGFBP-3 proteolysis and age. Plasma levels of IGF-I and -II were significantly lower in patients with elevated IGFBP-3 proteolysis compared to those within the normal range. Our findings reveal alterations in the IGF-system among a substantial number of patients with large primary breast cancers.     

胃癌合并糖尿病患者血清IGF-1和IGFBP-3水平的变化及意义

目的探讨胃癌合并糖尿病患者血清胰岛素样生长因子-1(IGF-1)和胰岛素样生长因子结合蛋白-3(IGFBP-3)的变化及其临床意义。方法选取2017年3月至2018年12月间收治的100例胃癌患者,按照是否合并糖尿病进行分组,其中,合并糖尿病的55例患者纳入糖尿病合并胃癌组,未合并糖尿病的45例患者纳入单纯胃癌组,比较两组患者的血清IGF-1和IGFBP-3水平。结果糖尿病合并胃癌组IGF-1和IGFBP-3阳性率显著较单纯胃癌组高,差异均有统计学意义(均P <0. 05)。糖尿病合并胃癌组IGF-1和IGF-1/IGFBP-3水平显著高于单纯胃癌组,差异均有统计学意义(均P <0. 05),两组患者IGFBP-3组间比较,差异无统计学意义(P> 0. 05)。糖尿病合并胃癌组空腹血糖、餐后2h血糖和糖化血红蛋白显著高于单纯胃癌组,差异均有统计学意义(均P <0. 05)。IGF-1与IGFBP-3呈正相关,差异有统计学意义(P <0. 05)。将以上影响因素纳入多因素分析,结果表明,IGF-1、IGFBP-3、IGF-1/IGFBP-3、空腹血糖和糖化血红蛋白是糖尿病合并胃癌发生的危险因素,差异均有统计学意义(均P <0. 05),餐后2h血糖对糖尿病合并胃癌发生无明显影响,差异无统计学意义(P> 0. 05)。结论 IGF-1和IGFBP-3均参与糖尿病合并胃癌疾病发生过程,其值对于预测病情发展具有一定作用。     

Prostate-specific antigen and insulin-like growth factor binding protein-3 in nipple aspirate fluid are associated with breast cancer

Insulin-like growth factor-1 (IGF-1) is an important growth factor for breast cancer cells and insulin-like growth factor binding protein-3 (IGFBP-3) its most prevalent binding protein. Prostate-specific antigen (PSA) enzymatically cleaves IGFBP-3 into fragments (BP3-FR). Our purpose was to determine the association of these markers in nipple aspirate fluid (NAF) and serum with the presence of breast cancer. NAF from 175 and serum from 215 subjects were collected from women with or without breast cancer. In unadjusted analysis low NAFPSA (P < 0.001) and high NAFIGFBP-3 (P = 0.023) were associated with breast cancer. Low serum PSA was associated with postmenopausal breast cancer (P = 0.034). In separate multivariate analyses, controlling for age, menopausal status, and age at menarche, NAF PSA and IGFBP-3 were each associated with breast cancer. The association was significant for NAF IGFBP-3 in all women (P = 0.031), but for NAF PSA only in premenopausal women (P < 0.001). When considered jointly, only NAF PSA was significant. Therefore, NAF PSA, and to a lesser extent NAF IGFBP-3 and serum PSA, seem to be important predictors of breast cancer.     

Genetically predicted high circulating insulin-like growth factor-1 and insulin-like growth factor binding protein-3 increase the risks of soft tissue sarcoma

Insulin growth factor-1 (IGF-1) plays important roles in carcinogenesis. Previous studies have linked circulating IGF-1 and its main binding protein, insulin-like growth factor-binding protein-3 (IGFBP-3), to cancer risks. However, no study has been conducted in soft tissue sarcoma (STS). In this study, we investigated the relationship of genetically predicted circulating IGF-1 and IGFBP-3 with STS risks. Recent large genome-wide association studies (GWAS) have identified 413 single nucleotide polymorphisms (SNPs) associated with IGF-1 and 4 SNPs associated with IGFBP-3. We genotyped these SNPs in 821 patients and 851 healthy controls. We constructed weighted genetic risk scores (GRS) to predict circulating IGF-1 and IGFBP-3. We determined the associations of individual SNPs and GRS with the risks of STS using multivariate logistic regression analysis. We found high genetically predicted circulating IGF-1 and IGFBP-3 were both associated with increased STS risks. Dichotomized at the median values of IGF-1 and IGFBP-3 in controls, individuals with high level of IGF-1 exhibited a 27% increased risk of STS (odds ratio [OR]=1.27, 95% confidence interval [CI]=1.04-1.54, P=0.017), whereas the OR for high IGFBP-3 was 1.45 (95% CI=1.20-1.77, P<0.001). Interestingly, the significant association between IGFBP-3 and STS risk was only evident in women (OR=1.88, 95% CI=1.42-2.49, P<0.001), but not in men (OR=1.00, 95% CI=0.75-1.33, P=0.992). In stratified analyses by major STS subtypes, the strongest associations were observed in angiosarcoma for IGF-1, leiomyosarcoma for IGFBP-3, and gastrointestinal stromal tumors for IGFBP-3 in women. In conclusion, high circulating IGF-1 and IGFBP-3 levels were both associated with increased STS risks.     

Insulin-like growth factor type 1 (IGF-1) and IGF binding protein-3 in patients with Ewing sarcoma family of tumors.

BACKGROUND: Ewing sarcoma family of tumors (ESFTs) are the second most common bone tumor, that most often affects persons ages 3-40 years. The ESFTs rely on signaling through the insulin-like growth factor-1 receptor (IGF-1R) for growth and transformation. The current studies were performed to determine the levels of IGF-1 and IGF binding protein-3 (IGFBP-3) in patients with ESFT. The authors then performed an exploratory analysis to evaluate whether IGF parameters could differentiate event free or overall survival in ESFT patients. METHODS: The authors measured serum levels of IGF-1 and IGFBP-3 by using a radioimmunoassay from 111 patients with ESFT with a median follow-up of 13 years from diagnosis. RESULTS: The IGF-1 levels were lower among patients with metastatic disease to the bones or the bone marrow compared with patients without metastasis to these sites (p2 = 0.021 and 0.0038, respectively). IGFBP-3 is known to sequester IGF-1; the ratios of IGFBP-3 to IGF-1 were evaluated. Patients with metastatic disease to any site had higher IGFBP-3 to IGF-1 ratios than patients with localized disease (p2 = 0.0067). There was a trend toward increased survival in patients with localized disease who had high IGFBP-3 to IGF-1 levels. Metastatic patients showed a similar trend. CONCLUSIONS: Levels of IGF-1 and IGFBP-3 in ESFT patients can identify patients with the most widespread disease. The IGFBP-3 to IGF-1 ratio in patients with either localized or metastatic disease identified patients with a trend toward increased survival. Further prospective evaluation with higher patient numbers might show a prognostic role for the IGFBP-3 to IGF-1 ratio in patients with ESFT.     

Insulin-like growth factor-1, insulin-like growth factor binding protein-3 and lobule type in the Nurses' Health Study II

Introduction

Previous research in the Nurses' Health Study (NHS) and the NHSII observed that, among women diagnosed with benign breast disease (BBD), those with predominant type 1/no type 3 lobules (a marker of complete involution) versus other lobule types were at lower risk of subsequent breast cancer. Studies in animal models suggest that insulin-like growth factor-1 (IGF-1) may inhibit involution of lobules in the breast; however, this has not been studied in humans.

Methods

We conducted a cross-sectional study among 472 women in the NHSII who were diagnosed with biopsy-confirmed proliferative BBD between 1991 and 2002 and provided blood samples between 1996 and 1999. A pathologist, blinded to exposure status, classified lobule type in normal adjacent tissue on available biopsy slides according to the number of acini per lobule. For each participant, the pathologist determined the predominant lobule type (that is, type 1, type 2, or type 3) and whether any type 1 or any type 3 lobules were present. Lobule type was then classified as: predominant type 1/no type 3 lobules, which is suggestive of complete involution; or other lobule types. Multivariate logistic models were used to assess the associations between plasma IGF-1, insulin-like growth factor binding protein-3 (IGFBP-3), and the ratio of IGF-1:IGFBP-3 levels with lobule type.

Results

In univariate analyses, greater age, higher body mass index, postmenopausal status, nulliparity, and lower IGF-1 levels were associated with predominant type 1/no type 3 lobules (P < 0.05). In multivariate models adjusting for age and assay batch, higher IGF-1 levels were associated with decreased odds of predominant type 1/no type 3 lobules (odds ratio quartile 4 vs. quartile 1 = 0.37, 95% confidence interval = 0.15 to 0.89). Greater ratios of IGF-1:IGFBP-3 levels were also associated with decreased odds of predominant type 1/no type 3 lobules (odds ratio quartile 4 vs. quartile 1 = 0.26, 95% confidence interval = 0.11 to 0.64). These results were slightly attenuated after adjustment for other potential predictors of lobule type.

Conclusions

Higher IGF-1 levels and a greater IGF-1:IGFBP-3 ratio were associated with decreased odds of having predominant type 1 lobules/no type 3 lobules among women with proliferative BBD in the NHSII. This study provides further evidence for the role of insulin-like growth factors in the structure of breast lobules and lobular involution.     

Elevated serum insulin-like growth factor binding protein-2 as a prognostic marker in patients with ovarian cancer.

PURPOSE: The purpose of this research was to examine the diagnostic and prognostic significance of elevated serum insulin-like growth factor binding protein (IGFBP)-2 levels in women with ovarian cancer from diagnosis through treatment to relapse or remission. EXPERIMENTAL DESIGN: Serum collected pre- and postoperatively in women newly diagnosed with ovarian cancer, during adjuvant chemotherapy cycles, at 6 months follow-up and at relapse was analyzed for IGFBP-2. Control serum was from women undergoing pelvic or abdominal surgery for benign ovarian disease or nonovarian pathology. RESULTS: IGFBP-2 at diagnosis was significantly elevated (P < 0.0001) in women with ovarian cancer (887 +/- 62 ng/ml) compared with benign controls (337 +/- 25 ng/ml), and women undergoing nonovarian surgery (439 +/- 49 ng/ml) and correlated positively with tumor stage and cellular differentiation but not with CA125. Unexpectedly, IGFBP-2 levels increased additionally 1-week postoperatively in ovarian cancer patients (1581 +/- 90 ng/ml; P = 0.0027) as well as controls (977 +/- 95 ng/ml; P < 0.0001) and was higher in women who had suboptimal debulking compared with optimal debulking of their tumor. IGFBP-2 levels returned to normal in women without evidence of progressive disease, but remained significantly elevated in women who later relapsed. Patients with IGFBP-2 levels in the highest tertile at diagnosis had a significantly shorter progression-free interval and overall survival. CONCLUSION: In ovarian cancer IGFBP-2 is elevated at diagnosis, and corresponds to stage and histology with patients in the highest tertile of IGFBP-2 more likely to relapse and have a poorer outlook. Identification of these patients at diagnosis may allow more individualized, aggressive adjuvant treatment and follow-up, and IGFBP-2 may therefore be an important additional prognostic marker in this disease.     

Factors associated with circulating levels of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in 740 women at risk for breast cancer

Prospective studies have shown an association between elevated plasma levels of insulin-like growth factor-I (IGF-I) and/or decreased levels of its major circulating carrier protein insulin-like growth factor binding protein-3 (IGFBP-3) and increased risk of major cancers. Identifying the factors which affect these biomarkers is of particular interest as subjects at increased risk could benefit from lifestyle changes, and/or chemoprevention intervention. We evaluated the association between constitutional, hormonal and clinical factors and IGF-I and IGFBP-3 in 740 women, including 376 unaffected women and 364 women with intraepithelial neoplasia (IEN) or early invasive breast cancer enrolled in breast cancer chemoprevention trials, conducted at a single institution. Age, body mass index (BMI), height, waist to hip girth ratio (WHR), parity, menopausal status, age at menarche, number of affected first degree relatives, number of biopsies and breast cancer status were considered in the analysis. Women with early breast cancer had 21% higher IGF-I levels ( p=0.033) and 19% higher IGF-I/IGFBP-3 molar ratio ( p=0.047) than unaffected women. In unaffected women, age was negatively associated with IGF-I ( p=0.002) and IGF-I/IGFBP-3 ( p=0.001), while age at menarche was negatively associated with IGFBP-3 levels ( p=0.043). In women with IEN or early breast cancer, IGF-I levels were negatively associated with age ( p < 0.001), and positively associated with prior biopsies for benign disease ( p=0.013), while age, parity and menopausal status were significant predictors of IGF-I/IGFBP-3 molar ratio. We conclude that circulating IGF-I levels are higher in women with prior breast cancer compared to unaffected women, and that IGF-I and/or IGFBP-3 levels are influenced by age and by reproductive and hormonal factors. These findings support their putative role as breast cancer risk biomarker.