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Genetic Polymorphisms Involved in Insulin-like Growth Factor (IGF) Pathway in Relation to Mammographic Breast Density and IGF Levels

¹ Breast Cancer Functional Genomics Group and McGill Centre for Bioinformatics, McGill University; ² Departments of Medicine and Oncology, Cancer Prevention Research Unit, Lady Davis Institute of the Jewish General Hospital and McGill University, Montreal, Quebec, Canada and ³ Département de Médecine Sociale et Préventive, Université Laval; ⁴ Unité de Recherche en Santé des Populations and ⁵ Centre des Maladies du Sein Deschênes-Fabia, Centre Hospitalier Affilié Universitaire de Québec, Quebec, Canada

Requests for reprints: Caroline Diorio, Unité de Recherche en Santé des Populations, Centre Hospitalier Affilié Universitaire de Québec, Hôpital Saint-Sacrement, 1050 Chemin Sainte-Foy, Quebec, Quebec, Canada G1S 4L8. Phone: 418-682-7390; Fax: 418-682-7949. E-mail: caroline.diorio{at}uresp.ulaval.ca

The insulin-like growth factor (IGF) pathway is believed to play a role in carcinogenesis of the mammary gland. Single nucleotide polymorphisms (SNPs) of IGF-I, IGF-binding protein-3 (IGFBP-3), IGF receptor 1, insulin receptor substrate 1, and phosphoinositide-3-kinase, catalytic, β polypeptide genes, which are members of the IGF pathway, have been associated with risk of common cancers, breast density, and/or IGF levels but results remain inconclusive. Thus, we evaluated the association of 11 targeted IGF pathway SNPs with circulating IGF levels and mammographic breast density. Among 741 white premenopausal women, blood samples were collected at time of screening mammography, and plasma IGF-I and IGFBP-3 levels were measured by ELISA. Percent and absolute breast density were estimated using a computer-assisted method. Multivariate linear models were used to examine the associations. Women carrying increasing number of copies of the rare allele of IGF-I rs1520220 and rs6220 SNPs had increased percent breast density (P_trend = 0.04 and 0.06, respectively). Carriers of increasing number of copies of the rare allele of phosphoinositide-3-kinase, catalytic, β polypeptide rs361072 SNP had decreased percent (P_trend = 0.04) and absolute (P_trend = 0.02) breast density. An association of insulin receptor substrate 1 rs1801278 SNP with absolute density (P_trend = 0.03) was also observed. All four IGFBP-3 SNPs (including rs2854744) were associated with IGF-I and IGFBP-3 levels. This study shows that several components of the IGF pathway are associated with breast density or IGF levels. Our findings provide additional support for the idea that several components of the IGF pathway may affect breast cancer risk and that this effect on breast cancer development may be mediated, at least in part, through its influence on the morphogenesis of breast tissue. (Cancer Epidemiol Biomarkers Prev 2008;17(4):880–8)