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Linking Physical Activity to Breast Cancer Risk via the Insulin/Insulin-like Growth Factor Signaling System, Part 2: The Effect of Insulin/Insulin-like Growth Factor Signaling on Breast Cancer Risk.

ABSTRACT: Perturbation of the insulin/insulin-like growth factor (IGF) signaling system is often cited as a mechanism driving breast cancer risk. A systematic review identified prospective cohort studies and Mendelian randomization studies that examined the effects of insulin/IGF signaling (IGF, their binding proteins (IGFBP), and markers of insulin resistance] on breast cancer risk. Meta-analyses generated effect estimates; risk of bias was assessed and the Grading of Recommendations Assessment, Development and Evaluation system applied to evaluate the overall quality of the evidence. Four Mendelian randomization and 19 prospective cohort studies met our inclusion criteria. Meta-analysis of cohort studies confirmed that higher IGF-1 increased risk of breast cancer; this finding was supported by the Mendelian randomization studies. IGFBP-3 did not affect breast cancer. Meta analyses for connecting-peptide and fasting insulin showed small risk increases, but confidence intervals were wide and crossed the null. The quality of evidence obtained ranged from 'very low' to 'moderate'. There were insufficient studies to examine other markers of insulin/IGF signaling. These findings do not strongly support the biological plausibility of the second part of the physical activity-insulin/IGF signaling system-breast cancer pathway. Robust conclusions cannot be drawn due to the dearth of high quality studies. See related article by Swain et al., p. 2106.

SUBMITTER: Drummond AE

PROVIDER: S-EPMC7613928 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Linking Physical Activity to Breast Cancer Risk via the Insulin/Insulin-like Growth Factor Signaling System, Part 2: The Effect of Insulin/Insulin-like Growth Factor Signaling on Breast Cancer Risk.

Drummond Ann E AE Swain Christopher T V CTV Milne Roger L RL English Dallas R DR Brown Kristy A KA Skinner Tina L TL Lay Jannelle J van Roekel Eline H EH Moore Melissa M MM Gaunt Tom R TR Martin Richard M RM Lewis Sarah J SJ Lynch Brigid M BM

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20221201 12

Perturbation of the insulin/insulin-like growth factor (IGF) signaling system is often cited as a mechanism driving breast cancer risk. A systematic review identified prospective cohort studies and Mendelian randomization studies that examined the effects of insulin/IGF signaling (IGF, their binding proteins (IGFBP), and markers of insulin resistance] on breast cancer risk. Meta-analyses generated effect estimates; risk of bias was assessed and the Grading of Recommendations Assessment, Developm ...[more]

PMID: 36464995

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Project description:Women who carry mutations in BRCA1 and BRCA2 have a substantially increased risk of developing breast cancer as compared with the general population. However, risk estimates range from 20 to 80%, suggesting the presence of genetic and/or environmental risk modifiers. Based on extensive in vivo and in vitro studies, one important pathway for breast cancer pathogenesis may be the insulin-like growth factor (IGF) signaling pathway, which regulates both cellular proliferation and apoptosis. BRCA1 has been shown to directly interact with IGF signaling such that variants in this pathway may modify risk of cancer in women carrying BRCA mutations. In this study, we investigate the association of variants in genes involved in IGF signaling and risk of breast cancer in women who carry deleterious BRCA1 and BRCA2 mutations.A cohort of 1,665 adult, female mutation carriers, including 1,122 BRCA1 carriers (433 cases) and 543 BRCA2 carriers (238 cases) were genotyped for SNPs in IGF1, IGF1 receptor (IGF1R), IGF1 binding protein (IGFBP1, IGFBP2, IGFBP5), and IGF receptor substrate 1 (IRS1). Cox proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was assumed; and for single SNP analyses, no additivity assumptions were made.Among BRCA1 carriers, significant associations were found between risk of breast cancer and LD blocks in IGF1R (global P = 0.011 for LD block 2 and global P = 0.012 for LD block 11). Among BRCA2 carriers, an LD block in IGFBP2 (global P = 0.0145) was found to be associated with the time to breast cancer diagnosis. No significant LD block associations were found for the other investigated genes among BRCA1 and BRCA2 carriers.This is the first study to investigate the role of genetic variation in IGF signaling and breast cancer risk in women carrying deleterious mutations in BRCA1 and BRCA2. We identified significant associations in variants in IGF1R and IRS1 in BRCA1 carriers and in IGFBP2 in BRCA2 carriers. Although there is known to be interaction of BRCA1 and IGF signaling, further replication and identification of causal mechanisms are needed to better understand these associations.

Project description: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 allowed for 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 6711 women. For the MR analyses, genetic variants associated with circulating IGF-1 and IGF-binding protein-3 (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, 4360 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 a greater breast cancer risk (odds ratio = 1.05, 95% CI = 1.01-1.10; P = 0.02), with a similar effect estimate for estrogen-positive (ER+) tumours, but no effect found for estrogen-negative (ER-) tumours. Genetically-predicted IGFBP-3 concentrations were not associated with breast cancer risk (odds ratio per 1-standard deviation increment = 1.00, 95% CI = 0.97-1.04; P = 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.

Project description:The development and progression of the great majority of breast cancers (BCs) are mainly dependent on the biological action elicited by estrogens through the classical estrogen receptor (ER), as well as the alternate receptor named G-protein-coupled estrogen receptor (GPER). In addition to estrogens, other hormones and growth factors, including the insulin and insulin-like growth factor system (IIGFs), play a role in BC. IIGFs cooperates with estrogen signaling to generate a multilevel cross-communication that ultimately facilitates the transition toward aggressive and life-threatening BC phenotypes. In this regard, the majority of BC deaths are correlated with the formation of metastatic lesions at distant sites. A thorough scrutiny of the biological and biochemical events orchestrating metastasis formation and dissemination has shown that virtually all cell types within the tumor microenvironment work closely with BC cells to seed cancerous units at distant sites. By establishing an intricate scheme of paracrine interactions that lead to the expression of genes involved in metastasis initiation, progression, and virulence, the cross-talk between BC cells and the surrounding microenvironmental components does dictate tumor fate and patients' prognosis. Following (i) a description of the main microenvironmental events prompting BC metastases and (ii) a concise overview of estrogen and the IIGFs signaling and their major regulatory functions in BC, here we provide a comprehensive analysis of the most recent findings on the role of these transduction pathways toward metastatic dissemination. In particular, we focused our attention on the main microenvironmental targets of the estrogen-IIGFs interplay, and we recapitulated relevant molecular nodes that orientate shared biological responses fostering the metastatic program. On the basis of available studies, we propose that a functional cross-talk between estrogens and IIGFs, by affecting the BC microenvironment, may contribute to the metastatic process and may be regarded as a novel target for combination therapies aimed at preventing the metastatic evolution.

Dataset Information

Linking Physical Activity to Breast Cancer Risk via the Insulin/Insulin-like Growth Factor Signaling System, Part 2: The Effect of Insulin/Insulin-like Growth Factor Signaling on Breast Cancer Risk.

Publications

Linking Physical Activity to Breast Cancer Risk via the Insulin/Insulin-like Growth Factor Signaling System, Part 2: The Effect of Insulin/Insulin-like Growth Factor Signaling on Breast Cancer Risk.

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