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Breast Cancer Res. 2019 Jul 23;21(1):81. doi: 10.1186/s13058-019-1162-8.

Relationship of circulating insulin-like growth factor-I and binding proteins 1-7 with mammographic density among women undergoing image-guided diagnostic breast biopsy.

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National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Division of Health Policy and Management, College of Health Sciences, Korea University, Seoul, Republic of Korea.
National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Royal College of Surgeons in Ireland, Dublin, Ireland.
McGill University, Montreal, QC, Canada.
University of Vermont and Vermont Cancer Center, Burlington, VT, USA.
University of Hawaii, Honolulu, Hawaii, USA.
Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
University of California San Francisco, San Francisco, CA, USA.
Mayo Clinic, Jacksonville, FL, USA.



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.


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.


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).


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.


Breast density; Breast neoplasm; Insulin-like growth factor; Insulin-like growth factor binding proteins; Mammographic density

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