Breast Cancer Risk in Relation to Serum IGF-1, IGFBP-3, and Their Genetic Determinants: A Study Within the Europena Prospective into Cancer (EPIC)

摘要

IGF-I is a central hormone in the regulation of anabolic (growth) processes as a function of available energy and elementary substrates (e.g., essential amino acids), and has strongly mitogenic and anti-apoptotic activities. Results from in vitro studies and animal experiments show that, in excess, the anabolic signals by IGF-I can promote the development of tumors at various organ sites, and recent epidemiological studies have shown an increased breast cancer risk in women with elevated serum IGF-I, or with elevated levels of IGF-I for given levels of IGFBP-3, the major plasmatic IGF-binding protein. While nutritional status is one important determinant of circulating IGF-I levels, heritability studies have shown that, in well-nourished populations, a large part (40-60 %) of variation in IGF-I is (co) determined by genetic factors. To increase understanding of what are the major determinants of IGF-I levels, as well as cancer risk, we have conducted a study with the following objectives: 1. Confirm that elevated prediagnostic serum levels of IGF-I increase breast cancer risk, especially in premenopausal women; 2. Describe exhaustively existing polymorphisms, allele frequencies and haplotypes in 13 selected genes related to the secretion of growth hormone, and hence to the synthesis of IGF-I and IGFBP-3; and 3. Examine whether these genetic polymorphisms are related to significant increases or decreases in circulating levels of IGF-I and IGFBP-3, as well as in breast cancer risk. Our project is a large case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), using prediagnostic blood (serum and DNA) samples collected during 1992-1998, from 233,800 women in Western Europe.