Abstract
Mammographic density (MD) is one of the strongest known breast cancer risk factors. Estrogen and progestin therapy (EPT) has been associated with increases in MD, and is known to increase breast cancer risk possibly through increased proliferation of breast epithelial cells. It is possible that genetic factors modify the association between EPT and MD, and that certain genetic variants are particularly important in determining MD in hormone users. We evaluated the association between mammographic density and 340 SNPs (singular nucleotide polymorphisms) from about 30 putative genes in hormone metabolism / growth factor pathways among women who participated in the Norwegian Breast Cancer Screening Program (NBCSP) in 2004.
We assessed mammographic density on 2040 postmenopausal women aged 50–69 years using a computer assisted method (Madena, University of Southern California). We ran multiple regressions models (dominant and additive), adjusting for age, body mass index (BMI) with and without adjustments for multiple comparisons (the number of SNPs per gene). We stratified the postmenopausal women into current, past and never EPT users. For postmenopausal current EPT users there was an association between a variant in the prolactin gene (rs10946545) and MD (dominant model p=0.0002). This association was also present in women who were currently using norethisterone acetate (NETA) based EPT, a regimen common in Nordic countries. In past EPT users, we found that two variants in the catechol-O-methyltransferase gene (COMT; rs2239395 and rs5992500) were associated with MD (dominant model p=0.0112), but the association was no longer significant when we adjusted for multiple tests. Among current estrogen only users, there was an association between a variant in the cytochrome P450 gene (CYP1B1; rs4670813) and MD in current estrogen only users (dominant model p=0.0028). We also found an association between a variant in the vascular endothelial growth factor gene (VEGF; rs833052) and MD for current users of high dose NETA EPT (dominant model p=0.0021), while in low dose NETA EPT users a variant in the tumor necrosis factor gene (TNF; rs4947324) was associated with MD (dominant model p=0.0007).
We found some evidence that variants in the prolactin and COMT genes were associated with MD in current or past EPT users. We also found associations between genetic variants in TNF and MD in low dose NETA users, and between variants in VEGF and MD in high dose NETA users.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A87.
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