Circulating Insulin-Like Growth Factor-I and Binding Protein-3 and the Risk of Breast Cancer Laura Baglietto, 1,2 Dallas R. English, 1,2 John L. Hopper, 2 Howard A. Morris, 3 Wayne D. Tilley, 3,4 and Graham G. Giles 1,2 1 Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Victoria, Australia; 2 Centre for Molecular, Environmental, Genetic, and Analytical Epidemiology, University of Melbourne, Melbourne, Victoria, Australia; 3 Hanson Institute, Institute of Medical and Veterinary Science, Adelaide, South Australia, Australia; and 4 Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia Abstract 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 premeno- pausal 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 (sub- cohort) 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 concen- tration 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. (Cancer Epidemiol Biomarkers Prev 2007;16(4):763–8) Introduction Insulin-like growth factor I (IGF-I) is a peptide hormone involved in regulating human growth and development by stimulating cell proliferation and inhibiting apoptosis, with a recognizedeffectontumorgrowth(1).Inthecirculation,IGF-I binds mainly to IGF-binding protein-3 (IGFBP-3; refs. 2, 3), a protein with specific binding affinities to IGFs, which not only regulates the mitogenic action of IGFs and inhibits their antiapoptotic effect, but also has an IGF-independent inhibi- tory effect on cell growth (1). Theliteratureontherelationshipbetweenbreastcancerrisk and circulating concentrations of IGF-I and IGFBP-3 had indicated an increased risk for premenopausal women with increasinglevelsofIGF-IandIGFBP-3,butnoassociationwith risk for postmenopausal women (3-6). Recently, the European Prospective Investigation into Cancer and Nutrition (EPIC) analyzed data from 1,081 cases and 2,098 matched controls, approximately the same number of incident cases as all previous prospective studies combined, and reported that women with the highest circulating levels of total IGF-I or IGFBP-3 had a 40% increased risk for breast cancer diagnosed after age 50, but no evidence of increased risk before this age (7). Similarly, they found an association when they restricted the analysis to postmenopausal women at the time of blood collection, but observed no association in women who were premenopausal. Another recent report from the prospective Nurses’ Health Study II showed that IGF-I and IGFBP-3 were not associated with breast cancer risk in a large group of primarily premenopausal women (8). These findings reopen the debate about the age dependence of the associations between IGF-I and IGFBP-3 and breast cancer risk. WeinvestigatedIGF-IandIGFBP-3andbreastcancerriskin thewomenoftheMelbourneCollaborativeCohortStudywith the specific aim of determining how the associations might vary with age. Materials and Methods Subjects and Case-Cohort Design. The Melbourne Collab- orative Cohort Study is a prospective cohort study of 41,528 people (24,479 women) ages between 27 and 75 years at baseline (99.3% of whom were ages 40-69 years). Recruitment occurred between 1990 and 1994 in the Melbourne metropo- litan area. The details of the study have been published elsewhere (9). The Cancer Council Victoria’s Human Research Ethics Committee approved the study protocol. Subjects gave written consent to participate and for the investigators to obtain access to their medical records. All women who had a confirmed diagnosis of breast cancer before baseline (2%) were excluded, as were women who did not provide a blood sample (3%) and those taking hormone replacement therapy at baseline (17%), leaving 19,347 women eligible for the case-cohort study. All women first diagnosed with breast cancer between baseline and June 30, 2002 were includedinthestudysample,asdidarandomsample(hereafter calledthesubcohort)of2,031womenfromthecohort. 763 Cancer Epidemiol Biomarkers Prev 2007;16(4). April 2007 Received 11/14/06; revised 1/24/07; accepted 1/30/07. Grant support: This study was funded by grants from the National Health and Medical Research Council (251533, 209057) and The National Breast Cancer Foundation and was further supported by infrastructure provided by The Cancer Council Victoria. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Graham Giles, Cancer Epidemiology Centre, The Cancer Council Victoria, 1 Rathdowne Street, Carlton, Melbourne, Victoria 3053, Australia. Phone: 61-39635-5155; Fax: 61-39635-5330. E-mail: graham.giles@cancervic.org.au Copyright D 2007 American Association for Cancer Research. doi:10.1158/1055-9965.EPI-06-0960 Downloaded from http://aacrjournals.org/cebp/article-pdf/16/4/763/1745417/763.pdf by guest on 10 December 2023