IGF1 CA repeat polymorphisms, lifestyle factors and breast cancer risk in the Long Island Breast Cancer Study Project

Insulin-like growth factor I (IGF-I) is an important regulator of growth and differentiation and is a potent mitogen for human breast cancer cells. Recent investigations suggest an association between cytosine-adenine dinucleotide (CA)(n) repeat polymorphisms of the IGF1 gene and IGF-I levels and further evidence indicates that genotype may influence breast cancer risk. We assessed the relation between IGF1 (CA)(n) repeats and breast cancer, and evaluated modification of genotype effects according to traditional breast cancer risk factors in 1028 breast cancer cases and 1086 controls. An increased risk of breast cancer was seen for genotypes that included alleles with fewer than (CA)(19) repeats when compared to (CA)(19) repeat carriers, an association that was particularly strong among premenopausal women [odds ratio (OR) = 3.31; 95% confidence interval (CI) = 1.47, 7.48]. No significant association was observed between an IGF1 genotype with no (CA)(19) repeat compared to (CA)(19) repeat genotypes in either pre- or postmenopausal women overall. However, when traditional breast cancer risk factors were considered, premenopausal women with genotypes that lacked a (CA)(19) repeat had a nearly 60% increased risk of breast cancer among those who had ever used hormonal birth control, while never users had a significantly reduced risk (P-interaction = 0.01). Among postmenopausal women, those with genotypes lacking a (CA)(19) repeat allele had significantly increased breast cancer risk among subjects with a lower than median body mass index (BMI) (OR = 1.77 95% CI = 1.09, 2.87), while no association for IGF1 genotype was seen among women with a higher than median BMI (P-interaction = 0.04). Our results demonstrate a role for alleles with fewer than (CA)(19) repeats as a risk factor for breast cancer and also suggest that several traditional breast cancer risk factors modify the association of the IGF1 (CA)(19) repeat genotype.