Abstract
Genetic variants of insulin-like growth factor 1 (IGF1) pathway genes have been shown to be associated with breast density and IGF1 levels and, therefore, may also influence breast cancer risk via pro-survival signaling cascades. The aim of this study was to investigate associations between IGF1 pathway single nucleotide polymorphisms (SNPs) and breast cancer risk among European and East Asian women, and potential interactions with menopausal status and breast tumor subtype. Stratified analyses of 1,037 cases and 1,050 controls from a population-based case–control study were conducted to assess associations with breast cancer for 22 SNPs across 5 IGF1 pathway genes in European and East Asian women. Odds ratios were calculated using logistic regression in additive genetic models. Polytomous logistic regression was used to assess heterogeneity by breast tumor subtype. Two SNPs of the IGF1 gene (rs1019731 and rs12821878) were associated with breast cancer risk among European women. Four highly linked IGF1 SNPs (rs2288378, rs17727841, rs7136446, and rs7956547) were modified by menopausal status among East Asian women only and associated with postmenopausal breast cancers. The association between rs2288378 and breast cancer risk was also modified by breast tumor subtype among East Asian women. Several IGF1 polymorphisms were found to be associated with breast cancer risk and some of these associations were modified by menopausal status or breast tumor subtype. Such interactions should be considered when assessing the role of these variants in breast cancer etiology.
Highlights
The insulin-like growth factor 1 (IGF1) signaling pathway has been implicated in normal cell growth, development, and differentiation in the mammary gland and other tissues [1, 2]
Over 90% of circulating IGF1 is bound by IGFBPs, with most being bound to insulin-like growth factor binding protein 3 (IGFBP3) [3]
We examined the associations of 22 polymorphisms across five IGF1 pathway genes (IGF1, IGFBP3, insulin-like growth factor 1 receptor (IGF1R), insulin receptor substrate 1 (IRS1), and PI3KCB) with risk of breast cancer among women of European and East Asian descent
Summary
The insulin-like growth factor 1 (IGF1) signaling pathway has been implicated in normal cell growth, development, and differentiation in the mammary gland and other tissues [1, 2]. Stimulation by growth hormone (GH) results in the production of IGF1, primarily in the liver. While IGF1 mediates its action through the insulin-like growth factor 1 receptor (IGF1R), its IGF1-Related Genes and Breast Cancer bioavailability is regulated by its binding proteins (IGFBPs). Over 90% of circulating IGF1 is bound by IGFBPs, with most being bound to insulin-like growth factor binding protein 3 (IGFBP3) [3]. Downstream of IGF1R, signaling transmission by insulin receptor substrate 1 (IRS1) activates multiple intracellular signaling pathways that mediate the actions of IGF1. The two major pathways are the phosphoinositide 3-kinase (PI3K)/ protein kinase B (Akt) pathway and the Ras/mitogen-activated protein kinase (MAPK) pathway [4]
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