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

Abstract

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 BMI 2 -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/m 2 ) ( 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. Electronic supplementary material The online version of this article (10.1186/s13058-019-1162-8) contains supplementary material, which is available to authorized users.

Role of the IGF-1 Axis in Overcoming Resistance in Breast Cancer

“…With regard to the association between mammographic density and serum IGF-1, there are controversial findings: Diorio et al (2005) found a positive association in premenopausal women, but other studies did not support this result ( Rice et al, 2012 ; Rinaldi et al, 2014 ). Recently, Hada et al (2019) demonstrated a positive association between circulating IGFBP2 and mammographic density particularly among women with lower BMI, but no strong correlation with IGF-1.…”

Polyploid Adipose Stem Cells Shift the Balance of IGF1/IGFBP2 to Promote the Growth of Breast Cancer

“…The oncogenic activity of IGFBP2 can be explained by its IGFindependent activities: it possesses a functional integrin-binding domain, heparin binding domains and a nuclear localization signal motif as well, all contributing to cellular signaling leading to cell proliferation, migration, and angiogenesis (23). In case of benign proliferative breast diseases and various type of breast cancers, the level of IGFBP2 both in serum and tumor mass may be upregulated (24,25), moreover, IGFBP2 has proliferative effect on breast cancer cell lines (26) and it is associated with the endocrine resistance of breast cancer (27), which suggests that IGFBP2 is oncogenic and it is a potential biomarker (16). Based on IGFBP2 positivity of breast cancers, a DNA vaccine was designed, encoding HER-2/neu, IGFBP2 and insulin-like growth factor 1 receptor (IGF1R) as tumor associated antigens and it proved to be effective in preclinical trials.…”

Molecular regulation of phenolic compounds on IGF-1 signaling cascade in breast cancer

“…[46][47][48] The role of IGFBPs has been studied intensely for its association with breast cancer. [49][50][51] Contradictory to the widely reported role of IGFBPs, Probst-Hensch et al found that circulating IGFBP2 and 3 were profoundly expressed in breast cancers and may have a dependence on body weight and hormonal effect. 49 McCarthy et al found that there was a positive correlation between IGFBP3 and IGF-1 mRNAs in breast cancer cells and this association was not found in normal breast cells.…”