Insulin-like growth factor-1 (IGF-1), insulin-like growth factor-binding protein-3 (IGFBP-3) and breast cancer risk: observational and Mendelian randomization analyses

Abstract

BackgroundEpidemiological evidence supports a positive association between circulating insulin-like growth factor-1 (IGF-1) concentrations and breast cancer risk, but both the magnitude and causality of this relationship are uncertain. We conducted observational analyses with adjustment for regression dilution bias, and Mendelian randomization (MR) analyses to allow causal inference. Patients and methodsWe investigated the associations between circulating IGF-1 concentrations and incident breast cancer risk in 206,263 women in the UK Biobank. Multivariable hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models.HRs were corrected for regression dilution using repeat IGF-1 measures available in a subsample of 6,711 women. For the MR analyses, genetic variants associated with circulating IGF-1 and IGFBP-3 levels were identified and their association with breast cancer was examined with two-sample MR methods using genome-wide data from 122,977 cases and 105,974 controls. ResultsIn the UK Biobank, after a median follow-up of 7.1 years, 4,360 incident breast cancer cases occurred. In the multivariable-adjusted models corrected for regression dilution, higher IGF-1 concentrations were associated with a greater risk of breast cancer (HR per 5 nmol/L increment of IGF-1=1.11, 95%CI=1.07-1.16). Similar positive associations were found by follow-up time, menopausal status, body mass index, and other risk factors. In the MR analyses, a 5 nmol/L increment in genetically-predicted IGF-1 concentration was associated with greater breast cancer risk (odds ratio [OR]=1.05, 95%CI=1.01-1.10; Pvalue=0.02), with a similar effect estimate for estrogen positive (ER + ) tumors, but no effect found for estrogen negative (ER -) tumors. Genetically-predicted IGFBP-3 concentrations were not associated with breast cancer risk (OR per 1-SD increment=1.00, 95%CI=0.97-1.04; Pvalue=0.98). ConclusionOur results support a probable causal relationship between circulating IGF-1 concentrations and breast cancer, suggesting that interventions targeting the IGF pathway may be beneficial in preventing breast tumorigenesis.

Intermittent and Periodic Fasting, Hormones, and Cancer Prevention

“…PF and especially FMDs, because of their periodic use, limited burden on human subjects, and effects on IGF-1, insulin, glucose, IGFBP-1 and ketone bodies levels, have the potential for applications in cancer prevention and treatment [10,[133][134][135].…”

Visceral Adiposity and Cancer: Role in Pathogenesis and Prognosis

“…Insulin receptors are overexpressed in malignant epithelial cells of breast carcinoma [92] and IGF-1 receptors are overexpressed in many tumor cell types [19,95]. Notably, IGF-1 circulating level are positively associated with an increased risk of colorectal and prostate cancers, as well as with premenopausal breast cancer, although the strength of these associations varies by cancer site [100][101][102]. However, it is important to note that in some tissues IGF-1 synthesis is regulated by other hormones apart from GH [95].…”

Diabetes and Colorectal Cancer Risk: A New Look at Molecular Mechanisms and Potential Role of Novel Antidiabetic Agents

“…On the other hand, data on IGF-1 expression in CRC are ambiguous. While a number of studies implicate increased IGF-1 in CRC patients or a positive association of elevated IGF-1 with CRC risk [40][41][42], others demonstrated lower levels of this peptide in CRC [43][44][45]. However, it should be noted that CRC-induced cachexia and consequent impaired liver synthetic function could be the reasons for decreased IGF-1 levels.…”

“…IR can contribute to the enhanced effects of IGFs since hyperinsulinemia suppresses levels of IGF binding proteins (IGFBPs), thus increasing the bioavailability of IGFs [51]. However, such inhibitory effects of insulin on IGFBPs should not be observed as straightforward, since novel data indicate that IGFBPs themselves exhibit direct cellular effects, independently of IGFs, although so far conducted studies yielded mainly inconclusive results regarding the role of IGFBPs in CRC [42,[52][53][54].…”