Background: The Insulin-like Growth Factors (IGFs) system has been shown to have an important role in breast carcinogenesis due to its involvement in the regulation of cell proliferation, differentiation and apoptosis. Several studies have found an association between serum concentration of IGF-I and IGFBP-3 - its major binding protein - and breast cancer risk.

A single nucleotide polymorphism in the promoter region of the IGFBP-3 gene (rs2854744), located at position -202 from the transcription start site, results in reduced promoter activity and decreased IGFBP-3 levels. Some evidence of an association between this polymorphism and breast cancer risk has been reported.

Methods and results: We conducted a nested case-control study within the Italian Tamoxifen Chemoprevention Trial, a phase III double-blind placebo-controlled multicentric prevention trial involving 5,408 hysterectomized women aged 35–70 years, who had received either tamoxifen 20 mg/day or placebo for 5 years. After an initial median follow-up of 81.2 months, 79 subjects were diagnosed with breast cancer. Forty-six patients (cases) consented a blood withdrawal as well as 136 controls without breast cancer, randomly selected and matched for age (±2 years), randomization date (±6 months) and participating center.

We genotyped case and control subjects for IGFBP-3 -202A>C with a Taqman real time PCR method for allelic discrimination (Applied Biosystems).

The IGFBP-3 -202A>C genotype frequencies for AA, AC, CC were 46%, 43% and 11% respectively in breast cancer cases and 31%, 48%, 21% in controls. We found a significant trend for a higher frequency of A allele within breast cancer cases compared to unaffected control subjects (Ptrend=0.04). We observed an odds ratio of 0.35 (95% CI 0.12–1.02) for breast cancer in subjects with CC compared to AA genotype, while no further association was found after stratifying for age and treatment group.

Conclusions: We showed that in the analyzed population within the Italian Tamoxifen Chemoprevention Trial, the genotype frequencies for the IGFBP-3 -202 A allele were higher in breast cancer cases compared to unaffected control subjects at variance with other observations. These results suggest that variation at the polymorphic locus -202 in the IGFBP-3 gene might have an influence on breast cancer risk, although further studies are mandatory to clarify the direction of this association and the possible biological meaning and clinical implications.

Citation Information: Clin Cancer Res 2010;16(7 Suppl):B3