Insulin-Like Growth Factor-I, IGF-Binding Protein-3, and Mammographic Breast Density

Abstract

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 computerassisted 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 = À0.124; 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 = À0.039; 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 = À0.150; P = 0.016 and r s = À0.008; 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-1, growth hormone, and daily cycling estrogen are associated with mammographic density in premenopausal women

“…In the present study, we observed a positive association between IGFBP-3 and percent mammographic density, which is in contrast to others [3]. However, the association between IGFBP-3 and breast cancer risk may differ according to whether IGFBP-3 is measured as intact, fragmented or total [52].…”

“…Ovarian steroid hormones and growth factors, on the other hand, increase cellular proliferation in the breast, which may be reflected through mammographic density. Furthermore, the growth hormone (GH)-insulin-like growth factor-1 (IGF-1) signaling pathway, has been associated with breast cancer [2,3], and IGF-1 is suggested to influence cellular proliferation and inhibit apoptosis through the activation of PI3/Akt pathway, in both normal breast cells and breast cancer cell lines [4,5]. The level of IGF-1 is regulated by GH, and modulated by insulin-like growth factor-binding protein-3 (IGFBP-3).…”

Given breast cancer, does breast size matter? Data from a prospective breast cancer cohort

“…In line with this, Hartmann et al showed that the success rate of breast augmenting estrogen stimulation was dependent on a subsequent increase of IGF-1 concentrations in the women tested (42). Moreover, high IGF-1 levels have been linked to mammographic density in premenopausal women (43). Mammographic density is significantly associated with breast cancer mortality (44).…”

Common genetic variation of insulin-like growth factor-binding protein 1 (IGFBP-1), IGFBP-3, and acid labile subunit in relation to serum IGF-I levels and mammographic density

“…It has been suggested that elevated levels of IGF-I may increase breast density and thereby increase the risk of breast cancer. Several studies have shown that elevated circulating levels of IGF-I are directly associated with higher mammographic density in premenopausal women [7][8][9][10], although these findings were not confirmed in all studies [11][12][13]. The association of circulating IGF-I levels with mammographic density was not seen in postmenopausal women [7-9, 11, 12].…”

“…IGFBP-3 has also been shown to act independently from IGF-I by inducing apoptosis [16,17]. High circulating levels of IGFBP-3 have been shown to be related to lower mammographic density in premenopausal women [7][8][9], but not all studies confirm this [10,12]. In postmenopausal women no relation was found between IGFBP-3 levels and mammographic density [7][8][9].…”