Genetic variation and circulating levels of IGF-I and IGFBP-3 in relation to risk of proliferative benign breast disease

Xuefen Su, Graham A. Colditz, Walter C. Willett, Laura C. Collins, Stuart J. Schnitt, James L. Connolly, Michael N. Pollak, Bernard Rosner, Rulla M. Tamimi

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40 Scopus citations


Insulin-like growth factor-I (IGF-I) and its major binding protein IGFBP-3 have been implicated in breast carcinogenesis. We examined the associations between genetic variants and circulating levels of IGF-I and IGFBP-3 with proliferative benign breast disease (BBD), a marker of increased breast cancer risk, in the Nurses' Health Study II (NHSII). Participants were 359 pathology-confirmed proliferative BBD cases and 359 matched controls. Circulating IGF-I and IGFBP-3 levels were measured in blood samples collected between 1996 and 1999. Thirty single nucleotide polymorphisms (SNPs) in IGF-I, IGFBP-1, and IGFBP-3 genes were selected using a haplotype tagging approach and genotyped in cases and controls. Circulating IGF-I levels were not associated with proliferative BBD risk. Higher circulating IGFBP-3 levels were significantly associated with increased risk of proliferative BBD (highest vs. lowest quartile odds ratio (OR) [95% confidence interval (CI)], 1.70 (1.06-2.72); p-trend 5 0.03). The minor alleles of 2 IGFBP-3 SNPs were associated with lower proliferative BBD risk (homozygous variant vs. homozygous wild-type OR (95% CI): rs3110697: 0.6 (0.4-0.9), p-trend 5 0.02; rs2132570: 0.2 (0.1-0.6), p-trend 5 0.02). Three other IGFBP-3 SNPs (rs2854744, rs2960436 and rs2854746) were significantly associated with circulating IGFBP-3 levels (p < 0.01). Although these SNPs were not significantly associated with proliferative BBD risk, there was suggestive evidence that the alleles associated with higher circulating IGFBP-3 levels were also associated with higher risk of proliferative BBD. These results suggest that genetic variants and circulating levels of IGFBP-3 may play a role in the early stage of breast carcinogenesis.

Original languageEnglish
Pages (from-to)180-190
Number of pages11
JournalInternational Journal of Cancer
Issue number1
StatePublished - Jan 1 2010


  • Circulating levels
  • Genetic variation
  • IGF-I
  • IGFBP-3
  • Proliferative BBD

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