IGF-1 has been shown to promote proliferation of normal epithelial breast cells, and the IGF pathway has also been linked to
mammary carcinogenesis in animal models. We comprehensively examined the association between common genetic
variation in the IGF1, IGFBP1, and IGFBP3 genes in relation to circulating IGF-I and IGFBP-3 levels and breast cancer risk
within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). This analysis included 6,912 breast cancer cases and
8,891 matched controls (n = 6,410 for circulating IGF-I and 6,275 for circulating IGFBP-3 analyses) comprised primarily of
Caucasian women drawn from six large cohorts. Linkage disequilibrium and haplotype patterns were characterized in the
regions surrounding IGF1 and the genes coding for two of its binding proteins, IGFBP1 and IGFBP3. In total, thirty haplotypetagging
single nucleotide polymorphisms (htSNP) were selected to provide high coverage of common haplotypes; the
haplotype structure was defined across four haplotype blocks for IGF1 and three for IGFBP1 and IGFBP3. Specific IGF1 SNPs
individually accounted for up to 5% change in circulating IGF-I levels and individual IGFBP3 SNPs were associated up to 12%
change in circulating IGFBP-3 levels, but no associations were observed between these polymorphisms and breast cancer
risk. Logistic regression analyses found no associations between breast cancer and any htSNPs or haplotypes in IGF1, IGFBP1,
or IGFBP3. No effect modification was observed in analyses stratified by menopausal status, family history of breast cancer,
body mass index, or postmenopausal hormone therapy, or for analyses stratified by stage at diagnosis or hormone receptor
status. In summary, the impact of genetic variation in IGF1 and IGFBP3 on circulating IGF levels does not appear to
substantially influence breast cancer risk substantially among primarily Caucasian postmenopausal women.