Background: Mammographic density (MD) is a strong breast cancer risk factor that reflects fibroglandular and adipose tissue composition, but its biologic underpinnings are poorly understood. Insulin-like growth factor binding proteins (IGFBPs) are markers that may be associated with MD given their hypothesized role in breast carcinogenesis. IGFBPs sequester IGF-I, limiting its bioavailability. Prior studies have found positive associations between circulating IGF-I and the IGF-I:IGFBP-3 ratio and breast cancer risk. We evaluated the associations of IGF-I, IGFBP-3, and six other IGFBPs with MD.
Methods: Serum IGF measures were quantified in 296 women, ages 40-65, undergoing diagnostic image-guided breast biopsy. Volumetric density measures (MD-V) were assessed in pre-biopsy digital mammograms using single X-ray absorptiometry. Area density measures (MD-A) were estimated by computer-assisted thresholding software. Age, body mass index (BMI), and BMI2-adjusted linear regression models were used to examine associations of serum IGF measures with MD. Effect modification by BMI was also assessed.
Results: IGF-I and IGFBP-3 were not strongly associated with MD after BMI adjustment. In multivariable analyses among premenopausal women, IGFBP-2 was positively associated with both percent MD-V (β = 1.49, p value = 0.02) and MD-A (β = 1.55, p value = 0.05). Among postmenopausal women, positive relationships between IGFBP-2 and percent MD-V (β = 2.04, p = 0.003) were observed; the positive associations between IGFBP-2 and percent MD-V were stronger among lean women (BMI < 25 kg/m2) (β = 5.32, p = 0.0002; p interaction = 0.0003).
Conclusions: In this comprehensive study of IGFBPs and MD, we observed a novel positive association between IGFBP-2 and MD, particularly among women with lower BMI. In concert with in vitro studies suggesting a dual role of IGFBP-2 on breast tissue, promoting cell proliferation as well as inhibiting tumorigenesis, our findings suggest that further studies assessing the role of IGFBP-2 in breast tissue composition, in addition to IGF-1 and IGFBP-3, are warranted.
Keywords: Breast density; Breast neoplasm; Insulin-like growth factor; Insulin-like growth factor binding proteins; Mammographic density.