Insulin‐like growth factor‐I, insulin‐like growth factor binding protein‐3 and the risk of fibrocystic breast conditions among Chinese women

Abstract

We investigated whether circulating insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) levels are associated with the risk of fibrocystic breast conditions (FBC), in a case-control study nested within a randomized trial of breast self-examination conducted in Shanghai, China. Participants were enrolled during 1989-1991 and were followed over 10 years for the development of breast diseases. Controls (n 5 897) were frequency-matched by age to cases (n 5 451), who were diagnosed with FBC between 1995 and 2000. Circulating IGF-I and IGFBP-3 levels and their molar ratio were positively associated with risk of FBC. The odds ratios (ORs) and 95% confidence intervals (CI) for the upper fourth of the distribution compared to the lowest fourth for IGF-I, IGFBP3 and their molar ratio were 3.02 (2.02-4.52), 1.92 (1.37-2.71) and 2.26 (1.52-3.36), respectively. The strength of the association between IGF-I levels and FBC was attenuated after adjustment for IGFBP-3 and that for IGFBP-3 was largely eliminated after adjustment for IGF-I. Increasing levels of IGF-I were particularly associated with increasing risk of FBC with proliferative elements (ORs and 95% CIs for the 2nd, 3rd and upper fourth of the distribution of IGF-I: 3.13 (1.50-6.53), 4.57 (2.22-9.39) and 6.30 (3.08-12.89), compared with the lowest fourth. Our results suggest that elevated levels of IGF-I may contribute to the development of FBC. ' 2005 Wiley-Liss, Inc.Key words: insulin-like growth factor; insulin-like growth factor binding protein-3; breast cancer; fibrocystic breast conditions; Chinese Insulin-like growth factors (IGFs) are potent mitogenic and anti-apoptotic factors that regulate cell proliferation, differentiation and apoptosis. [1][2][3] The effect of IGFs is modulated by at least 6 high affinity IGF-binding proteins (IGFBPs); 4,5 greater than 95% of circulating IGF-I is complexed with IGFBP-3 and an acid-labile subunit. 6 The majority of IGF-I and IGFBPs are produced by the liver, the rest by a wide variety of tissues. 2 There are several reasons to suspect that the circulating levels of IGF-I and IGFBP-3 could influence breast cancer risk. In in vitro studies, IGF-I modulates gene expression and growth of the breast cancer cell line 8 Expression of IGF-I receptors affect responsiveness of MCF-7 cells to IGF-I and estradiol. 9 Evidence from breast cancer cell lines, experimental animal models and epidemiologic studies suggests that there is a synergistic effect between IGF-I and estrogens and androgens on cell proliferation and breast cancer risk. 10-14 Breast epithelial cells and stromal tissues have been shown to contain IGF-I and IGF-II proteins, [15][16][17][18]19 as well as IGFs mRNA 20,21 and IGF-I receptor. 22 In addition to modulation of IGF availability and action, IGFBPs have been shown to inhibit cellular growth [23][24][25][26] and IGF-I receptor activation, 27 and enhance apoptosis. 28,29 In a mouse mammary model, a reduced circulating IGF-I level delayed the onset of chemically and genet...