Genetic Variation in the Growth Hormone Synthesis Pathway in Relation to Circulating Insulin-Like Growth Factor-I, Insulin-Like Growth Factor Binding Protein-3, and Breast Cancer Risk: Results from the European Prospective Investigation into Cancer and Nutrition Study

Abstract

Insulin-like growth factor-I (IGF-I) stimulates cell proliferation and can enhance the development of tumors in different organs. Epidemiologic studies have shown that an elevated level of circulating IGF-I is associated to increased risk of breast cancer as well as other cancers. Genetic variants affecting the release or biological action of growth hormone (GH), the main stimulator of IGF-I production, may predict circulating levels of IGF-I and have an effect on cancer risk. We tested this hypothesis with a large case-control study of 807 breast cancer patients and 1,588 matched control subjects nested within the European Prospective Investigation into Cancer and Nutrition. We genotyped 22 common single nucleotide polymorphisms in 10 genes involved in GH production and action (GHRH, GHRHR, SST, SSTR1-SSTR5, POU1F1, and GH1), and in parallel, we measured serum levels of IGF-I and IGFBP-3, its major binding protein, in samples of cases and controls. SST and SSTR2 polymorphisms showed weak but statistically significant associations with breast cancer risk. SSTR5 polymorphisms were associated with IGF-I levels, whereas one polymorphism in GHRHR and one in POU1F1 were associated with IGFBP-3 levels. Our conclusion is that common genetic variation in the GH synthesis pathway, as measured by single nucleotide polymorphisms selected in the present study, is not a major determinant of IGF-I and IGFBP-3 circulating levels, and it does not play a major role in altering breast cancer risk.

Models of genetic susceptibility to breast cancer

“…A few candidate gene studies and linkage analyses have been performed for age at menopause (see, for example, te Velde and Pearson, 2002;Kok et al, 2005), but none have provided concrete evidence of any susceptibility genes. Other phenotypes with a genetic component that have also shown associations with breast cancer risk include body mass index, bone mineral density (Hunter et al, 2001), chromosomal radiosensitivity (Roberts et al, 1999), levels of insulinlike growth factor-I and their binding proteins (Canzian et al, 2005;Fletcher et al, 2005) and sex hormone levels (Jaquish et al, 1997;Key et al, 2002;Dunning et al, 2004).…”

The rs1466113 Polymorphism in the Somatostatin Receptor 2 Gene Is Associated with Obesity and Food Intake in a Mediterranean Population

“…Other studies analyzing SSTR2 polymorphisms and gene expression have focused on cancer [17][18][19] . Thus, in the European prospective Investigation into Cancer and Nutrition (EPIC) study, the rs1466113 polymorphism was significantly associated with lower risk of breast cancer [17] .…”

“…Thus, in the European prospective Investigation into Cancer and Nutrition (EPIC) study, the rs1466113 polymorphism was significantly associated with lower risk of breast cancer [17] . Further studies have even demonstrated that the enhanced expression of SSTR2 could inhibit the proliferation of breast cancer cells [20] .…”

Haplotype-Based Analysis of Common Variation in theAcetyl-CoA Carboxylase αGene and Breast Cancer Risk: A Case-Control Study Nested within the European Prospective Investigation into Cancer and Nutrition

“…DNA extraction and SNPs genotyping were done as described by Canzian et al (35). Briefly, genotyping of the selected htSNPs was done using the TaqMan technique on the ABI PRISM 7900 sequence detection system (Applied Biosystems, France).…”